microRNA control of interferons and interferon induced anti-viral activity

Molecular Immunology 56 (2013) 781–793

Contents lists available at ScienceDirect

Molecular Immunology journal homepage: www.elsevier.com/locate/molimm

Review

microRNA control of interferons and interferon induced anti-viral activity Lisa M. Sedger ∗ Australian School of Advanced Medicine, Macquarie University, NSW 2109, Australia

a r t i c l e

i n f o

Article history: Received 26 May 2013 Received in revised form 11 July 2013 Accepted 14 July 2013 Available online 23 August 2013 Keywords: Anti-viral Interferon Interferon-inducible microRNA (miR) Virus

a b s t r a c t Interferons (IFNs) are cytokines that are spontaneously produced in response to virus infection. They act by binding to IFN-receptors (IFN-R), which trigger JAK/STAT cell signalling and the subsequent induction of hundreds of IFN-inducible genes, including both protein-coding and microRNA genes. IFN-induced genes then act synergistically to prevent virus replication and create an anti-viral state. miRNA are therefore integral to the innate response to virus infection and are important components of IFN-mediated biology. On the other hand viruses also encode miRNAs that in some cases interfere directly with the IFN response to infection. This review summarizes the important roles of miRNAs in virus infection acting both as IFN-stimulated anti-viral molecules and as critical regulators of IFNs and IFN-stimulated genes. It also highlights how recent knowledge in RNA editing influence miRNA control of virus infection. © 2013 Elsevier Ltd. All rights reserved.

1. Introduction Interferons (IFN) comprise a diverse group of structurally unrelated molecules that are naturally produced in response to virus infection. These cytokines were called “interferons” simply because they “interfere” with virus replication. IFNs do this by acting in an autocrine manner, directly influencing the virus-infected cells in which they are produced. However, because they are secreted molecules, they can also simultaneously affect neighbouring uninfected cells to create an “anti-viral state” in surrounding uninfected cells. IFNs induce the expression of genes that are transcriptionally activated as a result of IFN-receptor (IFN-R) signalling. In mammalian cells there are hundreds of genes that are IFN-inducible (IFN-stimulated genes; ISG), and many, although not all of these molecules have functions that inhibit virus replication in some way or other (Sadler and Williams, 2008). While IFN research has historically focused on interferons themselves or on interferoninduced proteins, IFNs also influence the expression of a number of non-coding RNA genes, especially micro RNA (miRNA). Therefore IFNs, ISG, and miRNA, act synergistically to create a potent virus non-specific cellular environment that is non-permissive for

Abbreviations: ADAR, adenosine deaminase acting on RNA; APOBEC, apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like; IFN, interferon; IFN-R, interferon receptor; IRF, interferon regulatory factor; JAK, janus kinase; miR or miRNA, microRNA; NO, nitric oxide; OAS, oligo adenylate synthase; PKR, protein kinase R; RISC, RNA induced silencing complex; STAT, signal transducers and activators of transcription. ∗ Tel.: +9850 2735; fax: +9812 3600. E-mail address: [email protected] 0161-5890/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.molimm.2013.07.009

virus replication (Sedger et al., 1999) (REFS) and together these protein and RNA molecules comprise a cells innate response to virus infection. 2. microRNA (miR): biogenesis and functions microRNAs (miRNA or miR) are small non-coding RNAs that are generally 22 nucleotides in length. Although first described in nematodes (Lau et al., 2001; Lee and Ambros, 2001), they are highly homologous across diverse animal and plant phyla (Lagos-Quintana et al., 2001) and encoded within diverse viral genomes (Ding and Lu, 2011). Mammalian miRNA genes often exist as non-coding genes located within intergenic regions of genomes, but they also exist within both exonic and intronic regions of protein-coding genes (Kapinas and Delany, 2011), and alternate exon splicing can regulate the expression of intronic miRNA genes (Melamed et al., 2013). Most miRNA genes are transcriptionally controlled by RNA polymerase II, transcription factors (Brueckner et al., 2007; O’Donnell et al., 2005) and DNA methylation (Szenthe et al., 2013) (for review on miRNA gene regulation see (Breving and Esquela-Kerscher, 2010). Many miRNA are also post-transcriptionally regulated (Wulczyn et al., 2007) and infact miRNA biogenesis occurs in several steps, all of which are tightly controlled (Tran and Hutvagner, 2013). miRNA genes are present singly or in clusters and are initially expressed as a long pri-miRNA precursor molecules which range from hundreds to thousands of nucleotides in length (Rodriguez et al., 2004; Saini et al., 2007). Most pri-miRNAs are then trimmed by Drosha (aided by the dsRNA binding protein DGCR8 (DiGeorge syndrome critical region gene 8 and the nuclear microprocessor complex), into pre-miRNAs, that

782

L.M. Sedger / Molecular Immunology 56 (2013) 781–793

are shorter hairpin structures of about 70 nucleotides in length (Denli et al., 2005; Lee et al., 2003). Given that miRNA genes are generally located within introns, they can sometimes also give rise to pre-miRNAs via intron splicing events, i.e., independently of Drosha (Ruby et al., 2007). Pre-miRNA molecules are then exported out of the nucleus via association with nuclear export molecules such as exportin-5 and RAN-GTP (Yi et al., 2003). Outside the nucleus the pre-miRNA then associates with Dicer and TAR RNA-binding protein, to yield a short double-stranded 22nt miRNA duplex: miRNA-miRNA* (Lee et al., 2002; Zhang et al., 2002). Here, one strand of the miRNA complex is then loaded onto the Agonaute-2 protein and forms the minimal RNA Induced Silencing Complex (RISC) (Hutvágner and Zamore, 2002). Using the miRNA as a “guide”, a RISC mediates binding of the miRNA to complementary sequences located within target mRNAs (Hutvagner, 2005) which usually results in target gene silencing by mRNA degradation or translational inhibition (Fig. 1). In general the miRNA:mRNA homology dictates the target mRNA molecules’ fate (Zeng et al., 2003); complete nucleotide complementarity within the 7–8 nucleotide “seed sequence” usually results in mRNA cleavage (Valencia-Sanchez et al., 2006), whereas miRNA molecules with partial or incomplete complementarity frequently cause translational inhibition of the mRNA (Beilharz et al., 2009; Humphreys et al., 2005) (Fig. 1). Alternatively miRNAs can occasionally enhance RNA stability, and even enhance viral RNA replication. It is thought that they do this by shielding the mRNA template from RNAse degradation (Li et al., 2013a). It is believed that there are over 700 human genome encoded miRNA genes (there are over 1000 miRNA molecules and greater than 24,000 miRNA entries in the miRBase Registry (version 20: http://www.mirbase.org/) (Griffiths-Jones et al., 2008). In contrast, bioinformatics searches for miRNA seed sequence complementarity motifs within mRNAs indicate that there are thousands of genes with potential “target” sequences. Therefore miRNA can have multiple complementary target mRNAs and they are believed to control expression of up to two-thirds of all mammalian genes (Lewis et al., 2005; Xie et al., 2007). In this regard it is evident that the target sequences may lie within different regions of mammalian genes and as such miRNA can influence mRNA expression in a variety of ways (Fig. 1). Most commonly miRNA seed sequence

Fig. 1. miRNA seed sequence complementarity gene location effects. IFN-inducible gene expression results in mRNAs with classical features including 5 -untranslated regions (UTR) with CAP structures, introns and 3 -UTR with poly(A) termini. These mRNAs are then spliced and processed into mature mRNAs with contiguous proteincoding open reading frames (ORFs). However, miRNA may have seed sequence complementarity to any region of the unprocessed or mature mRNA. miRNAs can target the 3 -UTR (1), but they may also show complementarity to intronic regions including intron/exon junctions (2), exonic coding regions (3) or 5 -UTRs (4). The function of the miRNA is then largely dependent on the degree of complementarity with the target mRNA, with a complete match usually resulting in mRNA cleavage or degradations, and incomplete matches likely mediating mRNA translational inhibition.

complementarity lies within the 3 -untranslated regions (UTR) of genes (Lai, 2002; Lewis et al., 2005) and miRNA binding at this location usually results in RNA degradation or translational inhibition (depending on the extent of homology between the miRNA see region and mRNA target, as discussed above). miRNA seed region homology can also exist within introns of protein-coding genes (Ying and Lin, 2005), or reside within 5 -UTR regions of genes, and hence they can negatively directly influence transcriptional regulation of target genes, not just mRNA stability or expression (Abdelmohsen et al., 2008). Conversely, there are also now examples of 5 -UTR-binding miRNA that can enhance mRNA expression (Janowski et al., 2007; Li et al., 2007a) potentially acting to improve mRNA stability. In summary miRNA regulation of protein gene expression is highly influenced by the context and location of the miRNA seed sequence, and degree of complementary between the miRNA seed sequence and mRNA target sequence. With respect to virus infection, miRNA not only target cellular genes that function to permit or inhibit virus replication, but they can exhibit a direct anti-viral activity in their own right by targeting viral mRNAs (Lecellier et al., 2005) (see Table 1). Similar to cellular mRNAs, miRNA targeting viral open reading frames (ORFs) cause degradation of viral mRNAs to regulate virus replication. Thus miRNA are critical players in the regulation of viral and cellular gene expression and they constitute an independent layer of regulation of gene expression. This review will now summarize what is known about miRNAs as regulators of IFNs and IFN-inducible anti-viral effector molecules. 3. Interferons (Ifns) and miRNA 3.1. Type I IFNs and IFN-inducible miRNA IFNs were first defined as molecules released from virusinfected cells that act to inhibit virus replication (Isaacs and Lindenmann, 1957). They are produced by cells in response to viral nucleic acid, notably, but not exclusively, dsRNA, which is an intermediate nucleic acid produced during virus replication and therefore present within most virus infected cells. Interferons are also produced in response to artificial nucleic acids such as polyinosine-polycytidylic acid (polyI:C), a synthetic analogue of dsRNA (Hilleman, 1970; Richmond and Hamilton, 1969). The production of IFNs is largely transcriptional; they are not pre-formed and stored within cells. Their expression is rapid and dramatic, that is, they are quickly produced early after infection and often in large amounts. For many type I IFNs the process begins through viral nucleic acid acting as a ligand for intracellular Toll-like receptor (TLR) molecules, whereby dsDNA binds TLR-3, and ssRNA binds TLR-7. Since these TLRs are frequently present within endosomes they are present within the same sub-cellular compartment as viruses that enter cells via receptor mediated endocytosis (Jensen and Thomsen, 2012). TLRs then induce intracellular signalling involving Myeloid differentiation primary response gene (MyD88) or TIR-domain-containing adapter-inducing IFN␤ (TRIF), which results in the activation of IFN regulatory factor (IRF)-3, IRF-7, and Nuclear Factor-kappa beta (NF␬B), and the subsequent transcriptional activation of type-I IFN gene promoters, especially IFN␣ and IFN␤ (for review see Sasai and Yamamoto, 2013). However, IFN can be induced by other mechanisms, for example by retinoic-acid-inducible protein I (Rig-I) helicase and melanoma-differentiation-associated gene 5 (MDA5) detection of viral RNA present in the cytoplasm of virus-infected cells (Kato et al., 2006) (for review see Hovanessian, 2007). Either way, type I IFNs are quickly produced in virus-infected cells, by virtue of the cell “sensing” or detecting the presence of viral nucleic acid. IFN are categorized into three classes, dependent primarily on the receptor molecules that they interact with. Type I IFNs

L.M. Sedger / Molecular Immunology 56 (2013) 781–793

783

Table 1 Examples of known IFN-inducible cellular miRNA with viral genome specific anti-viral activity. Viral target HVC 3 -UTR

HIV 3 -UTR

miRNA

Regulation

miRNA function

References

miR-352 miR-431 miR-488

↑ by IFN␤

Regulates HCV gene expression

Pedersen et al. (2007)

miR-29a

↑ by IFN␥ (?)

Decreases HIV replication

Nathans et al. (2009) Reinsbach et al. (2012) and Schmitt et al. (2012)

comprises more than 14 different IFN␣ molecules, as well as IFN␤, IFN␦, IFN␧, IFN␬, IFNо and IFN␶, which all engage the type-I IFN␣/␤ receptor (R) complex (IFNAR) (Fensterl and Sen, 2009; Joshi et al., 1982) (see Fig. 2). This IFN-R is ubiquitously expressed on most mammalian cells (de Weerd and Nguyen, 2012). Although many of these type-I IFN molecules appear to have anti-viral activity, others do not appear to have this intrinsic ability, and, instead, seem to exert other biological functions including diverse roles in cell transformation, cancer cell biology and tumour immune surveillance (Chen et al., 2009; Diamond et al., 2011; Fuertes et al., 2011) and mucosal immunology (Xi et al., 2012). It should be noted however that different viruses are susceptible to multiple overlapping and different IFN-I induced antiviral gene products (Schoggins et al., 2011). Type II IFN is a single molecule, IFN␥, first called “immune interferon” because it is mainly produced by activated T lymphocytes and Natural Killer (NK) cells. IFN␥ binds to its own receptor, the IFN␥R (see Fig. 2) but not at all to IFNAR (Aguet et al., 1988; Celada

Fig. 2. miRNA control of IFN, IFN-signalling and IFN-inducible genes expression. Types I, II and III IFNs bind to the respective receptors. IFN receptor phosphorylation by JAK kinases results in STAT proteins being recruited to the receptor and phosphorylated. Phosphorylated STATs then dimerise. STAT-1/-2:IRF9 (ISGF3), or STAT-1 homodimers, bind to ISRE or GAS gene promoter elements, respectively. This results in transcriptional activation (or repression) of IFN-regulated genes including Mx, oligo-adenylate synthase (OAS), RNaseL, protein kinase R (PKR), etc., which have anti-viral activity. miRNA with homology to IFNs, IFN-Rs, or IFN signalling molecule mRNA sequences can down-regulate their expression (as indicated, red T) and hence influence IFN signalling. miRNA with homology to IFN-regulated genes also directly influence their expression. Conversely, the APOBEC cytodine deaminase impairs miRNA control of mRNA degradation (as indicated, black T). Of note, no miRNA have been described with specificity for IFN-receptor associated JAK and TYK kinase mRNAs, nor for IFN-inducible genes Mx and OAS mRNAs.

et al., 1985). Lastly, type III IFN have been discovered more recently and comprise IFN␭1, 2, and 3 (Kotenko et al., 2003; Sheppard et al., 2003). These molecules bind to the IFN␭ receptor 1 (also known as interleukin (IL)-28a) and IL-10R2 (Kotenko et al., 2003; Sheppard et al., 2003). Type III IFNs also exert direct anti-viral activity (Sheppard et al., 2003). Type I IFNs and virus infection can directly induce the expression of miRNAs. For example, both polyI:C (a dsRNA mimic) and IFN␤ induces the expression of miR-155 in murine macrophages (O’Connell et al., 2007). Of importance, several IFN-induced miRNAs have been shown to have direct anti-viral activity in their own right. For example, at least eight miRNA are expressed in response to IFN␤, display RNA sequence specificity with the human hepatitis C virus genome, and of these, miR-351, miR-431 and miR-488 can functionally inhibit HCV replication (Pedersen et al., 2007) (see Table 1). The virus genome sequence specificity was confirmed by mutational analysis of the miRNA target sequence which abolished the miRNA anti-HCV activity (Pedersen et al., 2007). Similarly miR-29a, which is also IFN␣/␤ inducible, has homology to the HIV genome 3 UTR (Nathans et al., 2009). Expression of miR-29a decreases HIV replication, whereas inhibiting the miR results in enhanced viral replication, whereby miR-29a-HIV mRNA localizes with endogenous RISC (Nathans et al., 2009). Thus that IFN-inducible miRNAs that interact with HCV and HIV genomes and limit virus replication, serve as clear examples that some miRNAs are directly anti-viral in their own right, and that miRNA comprise a critical component of the IFN response to infection. Interestingly, some of these miRNAs are inducible by IFNs even in the absence of virus infection. This suggests that they have additional functions independent of virus infection. In this regard it has recently been suggested that miR-29a is also involved in thymic involution (Papadopoulou et al., 2011). Viruses do not sit quietly ignoring IFNs and anti-viral miRNA. Both influenza virus NS1 and Vaccinia virus RNA-binding protein E3L act to impede RNA silencing in an attempt to try and regulate IFN-controlled miRNA innate anti-viral activity (Li et al., 2004). Furthermore, the Ebola virus Vp35 prevents dsRNA-mediated transcriptional activation of IFN␤ (Cárdenas et al., 2006) by interfering with the transcriptional activation of the essential IFN-inducing transcription factor IRF-3 gene (Basler et al., 2003). Vp35 also inhibits induction of IRF-3-dependent activation of IFN-␣4 (Basler et al., 2003) and the transcription of IFN-inducible protein ISG54 (Basler et al., 2000). In fact there are a large number of virally encoded molecules that subvert almost all aspects of IFN biology, but this topic is beyond the scope of this review. IFNs can also down-regulate the expression of certain miRNA. For example IFN␤ down-regulates the expression of miR-122 (Pedersen et al., 2007), and since miR-122 is present in high abundance in serum of pegylated-IFN treated hepatitis C virus patients (Su et al., 2011), this highlights the normal role of specific miRNA in regulating IFN expression levels. Another example is miR-466l which targets multiple IFN␣ sub-types (Li et al., 2012). Thus, miRNA can act either as inducers or repressors of IFN expression, as well as IFN-induced regulators of virus replication. It is important to note, however, that IFN themselves also directly regulate the

784

L.M. Sedger / Molecular Immunology 56 (2013) 781–793

expression of the miRNA biogenesis machinery. In fact it is known that type I IFNs post-transcriptionally repress Dicer protein production, in contrast to IFN␥, which induces Dicer expression (Wiesen and Tomasi, 2009). Furthermore, Dicer requires dsRNA and associated proteins for optimal RNase activity which itself results in the production of type-I IFNs (Kok et al., 2011). It is therefore not surprising that Dicer gene knock-out mice exhibit aberrant IFN expression and are more susceptible to virus infection (Ostermann et al., 2012). These examples serve to illustrate the intimate relationship between virus infection and IFNs and the regulation of miRNA gene expression, demonstrating that this extends to regulating the miRNA synthesis machinery. 3.2. Type II IFN (IFN) and IFN-inducible miRNA It has been estimated that IFN␥ directly regulates over 100 miRNAs in human cells (Reinsbach et al., 2012; Schmitt et al., 2012), many of the cellular targets of IFN␥-stimulated miRNA are unconfirmed and/or unknown. What is known, however, is that miR-29 is up-regulated by IFN␥ signalling through STAT-1, although this has not been demonstrated in the context of virus infection (Schmitt et al., 2012). Also, human natural killer cells express miR-520b in IFN␥-inducible manner and targets the NKG2D receptor (Yadav et al., 2009). Although this study examines primary human tumour cells, it is significant to virus infection because NKG2D is important for NK cell detection of virally infected cells (Cosman et al., 2001; Groh et al., 2001), and activated NK cells are major producers of IFN␥ in virus infection in vivo (Karupiah et al., 1990, 1993). Furthermore, miR-27a, miR-30a, miR-34a are all inducible by IFN␥, although they are not detectible until 72 h post stimulation and other miRNA are not present until 24 h. This implies that these IFNinduced miRNA genes are transcriptionally activated, or expressed indirectly as a result of the expression of IFN-inducible proteins(s) (Reinsbach et al., 2012). Moreover, this illustrates the coordinated expression of miRNA clusters, with very few miRNA being expressed independent of surrounding miRNA genes (Reinsbach et al., 2012), and is consistent with the fact that miRNA genes are often located together and transcriptionally regulated as a unit (for review of miRNA gene structure, see Kim and Nam, 2006). 3.3. Type III IFNs (IFN1, 2, 3) and IFN-inducible miRNA Type III IFNS comprise IFN␭1 (IL-29), IFN␭2 (IL-28A) an IFN␭3 (IL-28B) and are more recently discovered molecules, with similar activities to Type I IFNs (Donnelly and Kotenko, 2010). They are distantly related to type I IFNs but also to IL-10 (Uzé and Monneron, 2007). Similar to type I IFNs, IFN␭ expression is induced through TLR-9 stimulation by CpG DNA in plasmacytoid dendritic cells (DC), as well as TLR-4 stimulation by lipopolysaccharide (LPS) or TLR-3 stimulation by poly I:C in monocyte-derived DC (MDDC) (Coccia et al., 2004). However type III IFNs bind to a distinct IFN receptor, the IFN␭R1 (otherwise known as the IL-28R-IFN␭) which complexes with IL-10R2 (Sheppard et al., 2003). Signalling from this receptor complex induces TYK/JAK phosphorylation and activation of STAT molecule (Kotenko et al., 2003; Zhu et al., 2005) and activates an anti-viral state that is both independent and synergistic to IFN␣ (Kotenko et al., 2003; Zhou et al., 2007; Zhu et al., 2005). These type III IFNs are particularly effective against RNA viruses such as hepatitis C (Zhu et al., 2005). In fact, IFN␭3 is important for recovery from hepatitis C (Ge et al., 2009) and is a critical component of the response to IFN␣ and ribarvarin anti-viral therapy for hepatitis C (Suppiah et al., 2009) (for review see Asselah et al., 2010). Type III IFN gene promoter regions have been characterized and shown to contain classical IRF, IFN-stimulated response element (ISRE) and NF␬B binding sites (Osterlund et al., 2007), and they are known to be transcriptionally activated by TLR-3, TLR-7 and RIG-I

signalling (Osterlund et al., 2007), similar to type I IFNs. Type III IFN genes are also regulated by miRNAs. Bioinformatics predictions reveal multiple 3 -UTR sites for miRNA binding within the IFN␭1 gene sequence, and miR-548 has been experimentally shown to down-regulate the expression of IFN␭1 (Li et al., 2013b). Furthermore, miR-15a is up-regulated in vivo in mice treated with IFN␣ and IFN␭ for 16 weeks (Yuan et al., 2012). It is currently unknown whether this miRNA is directly regulated by transcriptional activation of IFN␭ or by an IFN␭-inducible molecule. 4. IFN-receptors, IFN-R signalling & miRNA 4.1. IFN-receptors miRNA are highly efficent regulators of IFN receptors expression and biology. The IFN-␣␤R (IFNAR) 3 UTR contains a miR-1231 target sequence that regulates IFNAR expression (Zhou et al., 2012a). Furthermore, this target sequence aligns within a 4-base pair insertion/deletion polymorphism (rs17875871) in IFNAR that is correlated with hepatitis virus B pathogenesis and hepatocellular carcinoma (Zhou et al., 2012a). miR-155 is arguably one of the most crucial miRNA regulating IFN biology. It is expressed in abundance within activated antigenspecific effector and memory CD8T cells (two of the main cells types to produce IFN␥) where it is required for optimal CD8+ T cell responses to viral and bacterial infection (Gracias et al., 2013). It is also a potent regulator of IFN␥R expression in CD4T cells, where it can alter CD4T cell subset differentiation (Banerjee et al., 2010). The role of miR-155 on IFN␥R expression was confirmed through the identification of a functional miR-155 target site in the 3 UTR of the IFN␥R␣ mRNA and the demonstration that reduced miR155 results in increased IFN␥R expression and IFN-responsiveness (Banerjee et al., 2010). Another example of miRNA regulation of IFNR has been reported in bovine systems, where miR-378 is predicted to target IFN␥R1 and miR-378 expression correlates with decreased IFN␥R1 protein (Ma et al., 2011). 4.2. JAK/STAT signalling IFN binding to IFNAR, IFN␥R, or IFN␭R, induces signalling via the Janus Kinases and signal transducers and activators of transcription (JAK/STAT) pathway. Upon IFN binding, the IFNAR receptor associated Janus Kinase (JAK) and tyrosine kinase (TYK) are activated and subsequently phosphorylate specific amino acids on the IFNAR. Like many cytokine receptors, the phosphorylated receptor then recruits STATs that are themselves phosphorylated by JAKs. There are seven STATs (STAT-1, -2, -3, -4, -5a, -5b, and -6) that are all important in cytokine receptor signalling (for reviews on STAT proteins see Levy and Darnell, 2002; O’Shea et al., 2013). STAT-1 and STAT-2, which hetero-dimerise, are the main STATs involved in IFNAR signalling, especially for IFNs anti-viral activity. This is shown by the observations that STAT-1−/− cells are insensitive to IFN␣ & IFN␥ (Meraz et al., 1996) and are more susceptible to viral infection (Durbin et al., 1996). Similarly, STAT-2 deficiency correlates with susceptibility to virus infection in humans (Hambleton et al., 2013). STAT-1 and STAT-2 are not only important for type I IFNs signalling, but also type III IFN anti-viral activity (Dumoutier et al., 2004; Zhou et al., 2007). In contrast, STAT-3 is more important in IL-6 signalling (Oh et al., 2011), STAT-4 and STAT-6 are involved in IFN-mediated immune deviation and T helper cell biology (Wei et al., 2010), and STAT-5 is critical for Th-2T cells and DC activation (Bell et al., 2011). STAT-1 and STAT-2 heterodimers associate with IRF-9 to form a complex known as the InterferonStimulated Gene Factor-3 (ISGF3) (Brierley and Fish, 2005; Darnell et al., 1994). This complex binds to interferon-stimulated response

L.M. Sedger / Molecular Immunology 56 (2013) 781–793

elements (ISRE) DNA sequence motifs that are present within the promoter regions of many IFN-regulated genes. As such the STAT molecules are important in many cytokine receptor signalling pathways, and they are regulated by negative regulatory proteins known as the suppressor of cytokine signalling (SOCS) proteins (Dimitriou et al., 2008). Finally, while other IFN-R triggered intracellular signalling pathways exist, involving involving MAPK, p38, ERK, PI3K/AKT (Platanias, 2005), their importance in anti-viral immunity is unknown and hence they will not be discussed further. To date there are no miRNA that have been described that specifically target the JAK or Tyk kinase genes. On the other hand there are several miRNAs which have been demonstrated to target STATs (for review see Kohanbash and Okada, 2012). With respect to IFNsignalling, STATs and anti-viral activity, the most significant miRNA are arguably those that regulate expression or activity of STAT-1, -2, and -4, since these molecules are key to innate IFN-mediated anti-viral activity. miR-155 appears to play a central role in STAT-1 and STAT-2 biology. First, inflammatory cytokines, including IFN␥, increases miR-155 in epithelial cells, consistent with the presence of STAT-1 binding sites within the 5 -promotor region of the miR155 gene and documented STAT-1 binding to the miR-155 5 UTR (Kutty et al., 2010). Second, miR-155 expression in human hepatocellular carcinoma cells (HepG2 cells) results in suppression of SOCS1 (Su et al., 2011), and this correlates with regulation of SOCS1 biology in DCs (Lu et al., 2011; Zhou et al., 2010). There is also a report of miR-155 increasing the phosphorylation of STAT-1 and STAT-3, with subsequent increases in MxA and ISG15 IFN-regulated antiviral genes, and ultimately greater anti-viral activity against hepatitis B virus (Su et al., 2011). miR-155 is upregulated in IL12- and IL-18-activated NK cells, rich in STAT-4, in mice infected with cytomegalovirus where it also regulates SOCS1 (Zawislak et al., 2013). Thus, miR-155 regulates SOCS-1 in T cells during subset differentiation and JAK/STAT signalling (Yao et al., 2012). However, miR-155 is not the only miRNA that regulates SOCS molecules. MiR-9 reduces SOCS-5, resulting in enhanced JAK/STAT activation, and, although the impact of miR-9 in virus infection is currently unknown, SOCS-5 is negatively associated with HIV infection and replication in T cells (Smith et al., 2010). This suggests that SOCS-5 may play a previously unappreciated role in host gene biology in a way that influences HIV biology and viral load (Smith et al., 2010). Other miRNA that regulate STATs are miR-221/222 and miR145 which alter STAT-1 and STAT-2 expression (Gregersen et al., 2010). However, the functions of these mRNAs have been documented with respect to modulation of gene expression important to tumours cells, rather than in virus infection per se. Also, miR-212, miR-132 and miR-200a can target STAT-4 via sequence homology its 3 -UTR (Huang et al., 2011). These are IL-12 inducible miRNAs, and their biological roles in anti-viral immunity is in their relation to IL-12-activated NK cells, whereby NK cell expressed miRNA correlates with NK cell inability to produce IFN␥ (Huang et al., 2011). Thus these miRNA are integral not only to the production of IFN␥ and effective anti-viral immunity, but also to IL-12-driven biology. 4.3. Interferon regulatory factors (IRFs) IRFs are transcription factors that bind to promoter regions of genes containing interferon signal response elements (ISRE) (Tanaka et al., 1993). Some IRFs function as transcriptional activators, whilst others are transcriptional repressors, depending on the context of their DNA binding. IRF-1 and IRF-2 bind to elements in multiple IFN-regulated genes, as well as within type I IFN (IFN-␣ and -␤) (Tanaka et al., 1993) and thus they are integral to the expression of IFN and to IFN-inducible genes (Tanaka et al., 1993). IRF-9, is particularly integral to the type I and III IFN signalling pathways as it forms a complex with STAT-1 and STAT-2, known as the interferon stimulated gene transcription factor-3 (ISGF3) complex. ISGF3 is

785

central to IFN-inducible genes (ISG) ISG-15, Mx, oligo-adenylate synthase (OAS) and protein kinase-R (PKR), amongst others, and hence regulation of IRF-9 by miRNA directly modulates IFNs antiviral activities. Similarly, IRF-3 and IRF-9 are important in type I IFN synthesis, including both basal and virus infection induced IFN expression. This is evident by the fact that IRF-3-gene deficient mice are more susceptible to virus infection, due primarily to a lack of production of infection-induced IFNs (Sato et al., 2000). As transcription factors, IRFs can also directly modulate miRNA gene expression. For example, experimental over-expression of IRF-3 suppresses the expression of miR-155 and miR-155* in primary human astrocytes (Tarassishin et al., 2011). However, in additional to IFN␥R mRNA (Banerjee et al., 2010), another direct target of miR-155 is the SOCS IFN-signalling regulatory molecule. Thus IRF-3 and miR-155 are involved in a direct feedback system to regulate IFN gene expression by modulating SOCS levels. This has recently been shown to be important for DC cell development (Lu et al., 2011) and in CD8T cell antiviral and anti-tumour activity (Dudda et al., 2013). As another example, IRF-1 maintains basal expression of miR-342 in haemopoietic cells whereas IRF-9 is involved in increased expression of miR-342 by all-trans-retinoic acid (De Marchis et al., 2009). Also, miR-125a and miR-125b are predicted to be able to bind to IRF-4, although only miR-125b has been demonstrated to directly bind to IRF-4 in B lymphocytes (Gururajan et al., 2010). These are recent findings and at present it is unknown whether these IRFs regulate thee same miRNA within the context of virus infection and IFN-mediated anti-viral activity. IRFs themselves can be directly or indirectly modulated by microRNA. For example, miR-22, a miRNA directly targeting high mobility group box-1 (HMGB1) and IRF-5, prevents activation of IRF-3 and NF-␬B, and thus ultimately reduces IFN gene expression (Polioudakis et al., 2013). Furthermore, HIV TAT expression in glial cells results in increased miR-32 expression, and since TRAF-3 is a direct target of miR-32, TRAF-3 levels then control IRF-3 and IRF-7 expression (Mishra et al., 2012). IRFs can also be influenced by virally encoded miRNAs. The virally associated latent miRNA transcripts produced during bovine herpesvirus 1 infection act with RNA-binding RIG-1 helicase and target IRF-3 and IRF-7 to stimulate the IFN␤ promoter and thus type I IFN production (Silva and Jones, 2012). IFN␤ production then correlates with the maintenance of latency during infection with this bovine herpes virus.

5. IFN-inducible genes and miRNA 5.1. Mx GTPase Mx proteins were first identified for their anti-viral activity against influenza (Lindenmann, 1962). They are GTPases comprising MxA and MxB in humans, and Mx1 and Mx2 in mice, and are highly inducible by both type I and type III IFNs (Holzinger et al., 2007; Meager et al., 2005). Genes encoding Mx molecules are not only present in vertebrates (Aebi et al., 1989; Hug et al., 1988) but also in invertebrates (De Zoysa et al., 2007) and as such they constitute an archetypical interferon-induced anti-viral response molecules. Mx proteins contribute significantly to the ability of IFNs to induce an “anti-viral state” (for reviews see Arnheiter and Haller, 1988; Haller et al., 2007). This is exemplified by the fact that deletion or mutation of the Mx gene results in greater susceptibility in mice to virus infection (Jin et al., 1999; Staeheli et al., 1988), and that expression of human Mx protein in IFNAR-deficient mice confers resistance to what would otherwise be a fatal virus infection (Arnheiter et al., 1990). Furthermore the human Mx gene equivalent, IFN-inducible gene-78K gene, is found on chromosome 21 (Reeves et al., 1988) and cells from humans with trisomy-21 are more resistant to virus infection – a classic Mx gene dose effect

786

L.M. Sedger / Molecular Immunology 56 (2013) 781–793

(Horisberger et al., 1988). The potent anti-influenza virus activity of Mx is also evident within avian cells (Garber et al., 1991). Since influenza is primarily an avian virus, this further identifies Mx as a highly significant endogenous anti-viral effector molecule. In fact it has been postulated that Mx genes serve as a barrier for natural human influenza infection, and that the absence of an effective Mx gene in domestic birds likely confers their susceptibility to pathogenic avian influenza virus (Haller et al., 2009). Therefore, the deliberate, possibly transgenic, expression of Mx genes within poultry of industry significance (that are otherwise devoid of these genes) is being discussed as way to provide resistance in an otherwise highly susceptible host, and thereby to protect them against highly pathogenic avian influenza (Haller et al., 2009). Indeed it was recently reported that differences in influenza nucleoprotein are present within pathogenic versus non-pathogenic influenza virus strains, and that this directly correlates with sensitivity to Mx-mediated protection from infection (Zimmermann et al., 2011). Thus the basis of pathogenicity of different influenza virus strains is, in many respects, the IFN-induced Mx-mediated antiviral activity. As stated, the Mx family proteins are GTPases, i.e. they are guanosine triphosphate (GTP)-binding proteins (Horisberger et al., 1990), inducible by IFNs (Holzinger et al., 2007; Meager et al., 2005) or infection with certain viruses – and in some cases independently of IFNs (Goetschy et al., 1989). They exert anti-viral activity, in part by blocking transcription, which limits viral gene expression (Turan et al., 2004; Weber et al., 2000), and also by detecting and binding to viral nucleocapsids which are then sequestered and unavailable for progeny virus morphogenesis (Kochs and Haller, 1999a, 1999b). It is notable that there are currently no miRNAs yet described that have homology with Mx gene sequences or that function to directly regulate Mx gene expression. miRNA regulation of Mx antiviral activity is therefore only influenced indirectly by miRNA targetting IFN levels, or IFN-specific signalling molecules involved in the induction of Mx protein expression. This may in fact highlight the necessity of innate endogenous inhibitors of viral replication, molecule such as the Mx GTPases. In other words, Mx-like functions are essential for IFN-mediated anti-viral activity and thus cell survival in a world where viruses are abundant and likely to be encountered at some point or other in time.

receptor proteins, facilitating its degradation and contributing to hypothyroidism, and thereby to chronic fatigue related to virus infection (Englebienne et al., 2003). OAS molecules are potently anti-viral. This is because the trimeric, active OAS complexes synthesize 2 ,-5 -linked oligoadenylates that activates the constitutively expressed but non-active RNaseL into an active RNase (Floyd-Smith et al., 1981; Nakanishi et al., 2005; Wreschner et al., 1981). The OAS enzymes are important host factors regulate the outcomes of virus infection. For example, in murine systems OAS enzymes are important host restriction factors limiting the outcome of virus infection, especially flavivirus infections (Kajaste-Rudnitski et al., 2006), including human hepatitis C virus (HCV) infection (Ishibashi et al., 2010; Kwon et al., 2013). Moreover, genotypes of OAS have been reported to correlate with outcomes of HCV infection (Knapp et al., 2003), liver fibrosis in chronic HCV infected patients (Li et al., 2009), and are linked to patient IFN-responsiveness during anti-HCV therapy (El Awady et al., 2011). No naturally occurring miRNAs have been described to date that have seed-sequence homology to OAS genes. Like Mx, this highlights OAS molecules as inherent and critically important innate anti-viral effector molecules, essential to cell survival during virus infection. However, siRNA have been designed to specifically target mystatin which have unexpectedly resulted in increased OAS1 and increased miR-21 expression (Stewart et al., 2008). miR-21 is purportedly a pro-survival factor, regulating a variety of cellular genes including programmed cell death 4 (PCD4) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) – a regulator of PI3Kinase/AKT signalling and tropomycin (Gu et al., 2013; Lv et al., 2013). miR-21 is up-regulated in myocardial cells of mice with coxsackievirus B3 (CVB3)-induced myocarditis (He et al., 2013). It turns out that even in this context, miR-21 also inhibits PCD4 expression (He et al., 2013), and thus it remains possible that miR-29 is related to IFN’s effects on cell survival rather than anti-viral activity. This highlights the importance of OAS and IFNs, not only as anti-viral effector molecules, but also in tumour biology and a variety of human cancers.

5.2. 2 ,5 -Oligoadenylate synthase (2 ,5 -OAS)

As already mentioned, RNAseL is a latent endoribonuclease that acts in the interferon-regulated RNA decay pathway involving 2 5-OAS (Zhou et al., 1993). It acts by binding to 2 -5-oligoadenylate, whereupon it becomes dimerized, and once active, it cleaves single stranded U-rich RNA, particularly those with UU or UA dinucleotides (Floyd-Smith et al., 1981; Wreschner et al., 1981). RNaseL expression is itself IFN-inducible (Rusch et al., 2000; Zhou et al., 1993). Furthermore, the small RNAs produced by RNaseL during viral infections activate RIG-1 helicases, that further amplifies the production of IFN-␤. RNaseL contributes both to interferon-induced anti-viral and anti-tumour activity (Xiang et al., 2003; Zhou et al., 1997) both by inhibiting cell proliferation and via its RNase activity on viral nucleic acid (for a review on the biochemical interactions and functions of RnaseL see Chakrabarti et al., 2011). RNaseL expression is post-transcriptionally regulated largely through elements within its 3 -UTR (Li et al., 2007b). Recently it has been demonstrated that miR-29 represses RNaseL expression via interaction with multiple sequences present in its 3 -UTR (Lee et al., 2012a). The motif in the 3 -UTR was confirmed by mutation analysis of the predicted miRNA homologous sites, all of which abrogate miR-29 repression of RNaseL (Lee et al., 2012a).

2 ,5 -Oligoadenylate synthase (OAS) generates 2 ,5 oligoadenylates which activate a latent RNAse known as RNAseL. Thus OAS and RNAseL are major mediators of dsRNA degradation in virus-infected cells. These molecules are therefore central to the detection of viral RNA, as the RNA degradation products are recognized by RIG-I helicase and MDA5 – the major cytoplasmic sensors of virus infection in mammalian cells (for review see Hovanessian, 2007). There are four OAs enzymes, OAS1, 2, 3 and OAS-L (OAS-like), although they are produced in various splice forms: OAS1 (p42, p44, p46, p48, and p52), OAS2 (p69 and p71), OAS3 (p100), and OASL (p30 and p59) (Hovnanian et al., 1999; Marié et al., 1990; Mashimo et al., 2003; Rebouillat et al., 1998) that localize in different compartments within virus infected cells (Lin et al., 2009). These molecules comprise different sub-units containing one, two or three OAS units, or in the case of OAS-L, just a single OAS domain and ubiquitin-like repeats (Hovanessian and Justesen, 2007). Interestingly, the OAS genes appear to be differentially regulated during virus infection (Melchjorsen et al., 2009), probably reflecting differential transcriptional control and/or distinct functions (Melchjorsen et al., 2009). They have also been postulated to act in post-viral chronic fatigue because OAS-L contains thyroid hormone receptor (TR) regulatory domains with high amino acid homology to thyroid receptor interacting proteins. Thus it has been hypothesed that OAS-L associates with thyroid

5.3. RNaseL

5.4. Protein kinase-R (PKR) Protein kinase-R is an IFN-inducible kinase and quintessential regulator of viral and cellular protein expression (Roberts et al.,

L.M. Sedger / Molecular Immunology 56 (2013) 781–793

1976). dsRNA (an intermediate of virus replication) is a direct activator of PKR, especially RNA longer than 30 nucleotides (Nanduri et al., 1998), as are type I and type III IFNs (Ank et al., 2006; Bandi et al., 2010). ssRNA can also activate PKR, but they must be at least 47 nucleotides in length, have limited tertiary structure and 5 tri-phosphate termini (Nallagatla et al., 2007). Even then, ssRNA activates PKR in a RIG-I- and IFN-dependent manner (Nallagatla et al., 2007). These single and double-stranded RNAs allow for selective viral RNA activation of PKR by virtue of the fact that cellular RNAs are generally 5 -monophosphate, whilst many viral RNAs are 5 -triphosphate (Nallagatla et al., 2007). PKR is also activated by caspase-3 and caspase-8 mediated cleavage of the PKR autoinhibitory domain (Gil and Esteban, 2000). PKR dimerization, autophosphorylation and activation, results in inhibition of protein synthesis by its ability to phosphorylate and inactivate the translation initiation factor eIF2␣ (for review see Pindel and Sadler, 2011). Thus basally expressed PKR is quickly up-regulated by type I and type III IFNs (Ank et al., 2006; Bandi et al., 2010) and is directly antiviral by preventing viral protein synthesis (Munir and Berg, 2013; Sadler and Williams, 2008). Therefore PKR is a potent IFN-inducible translational inhibitor of virus gene expression (Roberts et al., 1976). Consistent with this, mice deficient in PKR are susceptible to otherwise non-lethal virus infections (Balachandran et al., 2000; Stojdl et al., 2000) and humans with PKR gene polymorphisms are more severely affected by hepatitis C virus (Knapp et al., 2003). PKRs’ IFN-mediated induction is particularly sensitive to miRNA control, by both viral and cellular micro- and non-coding RNAs. For example, PKR expression levels are influenced by miRNAs that target and reduce IFN expression or those that minimize IFNR signalling. miRNA have also been reported to act directly on PKR. Here, precursor-miR-866 is capable of directly binding to PKR mRNA, and suppression of pre-miR-866 directly results in increased activation of cytoplasmic PKR levels and eIF2a phosphorylation (Lee et al., 2011). Interestingly, the association of this miRNA with PKR appears to play a role in setting the threshold for PKR activation, because the non-coding RNA competes with dsRNA and attenuates PKR activation by dsRNA (Jeon et al., 2012). In this sense miRNA control ensures that PKR activation occurs with significant levels of dsRNA, especially those representative of and in high abundance in virus-infected cells. Thus pre-miR-866 constitutes an extremely important regulator of PKR activation. Yet, the normal expression patterns of pre-miR-866 itself, is currently unknown. Nor is it known whether pre-miR-866 expression is influenced positively or negatively by IFNs, although a recent report suggests it may be present in reduced abundance in some cancer cells (Lee et al., 2011). The regulation of PKR may also occur through miRNA regulation of PKR-activating molecules. Although PKR is normally activated by dsRNA and endoreticulum (ER) stress, it is also known to be associated with and be activated by PKR-associated protein-X (RAX), which is up-regulated in growth-factor deprived and/or stressed cells (Ito et al., 1999). miR-29b has been reported to have sequence homology to RAX (Silva et al., 2011) and miR29b expression correlates with RAX levels – although a direct biochemical interaction between the two has not yet been shown (Silva et al., 2011). The expression of RAX in virus-infected cells is also yet to be investigated. However, given the impact of virus infection on most host cells, especially the shut-down of host cell protein synthesis in favour of viral gene expression, it is tempting to speculate that RAX and miR-29b are somehow involved with PKR activation during virus infection. It is well known that viruses encode proteins such as the poxvirus E3L and K3L proteins that interfere with and/or inactivate PKR (Langland et al., 2006), but PKR is also influenced by virally encoded miRNA. One of the best known of these virally encoded PKR regulating proteins is the HIV trans-activating response (TAR)

787

RNA-binding protein (TRBP) (Park et al., 1994) which regulates HIV gene expression by association with HIV TAR (Gatignol et al., 1991). In fact the TRBP-PKR interaction is deemed to be a significant control step in the regulation of HIV replication (Sanghvi and Steel, 2011). Nevertheless, TRBP also has RNA enhancing properties (Dorin et al., 2003) and directly interacts with Dicer to aid the cleavage of pre-miRNAs (Haase et al., 2005). Thus TRBP is both an inhibitor of interferon-inducible PKR and a regulator of miRNA biogenesis. Another virally encoded protein that blocks PKR and facilitates RNA silencing is the Ebola VP35 protein. VP35 directly inhibits PKR and although the mechanism(s) is not well understood, VP35 prevents the phosphorylation and PKR inactivation of eIF-2␣ (Feng et al., 2007; Schumann et al., 2009). VP35 is also an RNA silencing suppressor (Zhu et al., 2012), but unlike TRBP its RNA silencing activity is not dependent on RNA binding, and thus it probably acts by interacting with as yet unidentified RNA silencing proteins. 5.5. Nitric oxide (NO) Nitric oxide (NO) is produced by nitric oxide synthase (NOS) (Michel and Feron, 1997), an isoform of which, iNOS, is IFNinducible by virtue of a GAS element in the iNOS gene promoter (Gao et al., 1997). IFN␥-induced NO is important for controlling virus infection by limiting virus replication in macrophages by inducing macrophage cell death (Karupiah et al., 1993). It has recently been shown that iNOS mRNA contains 3 miRNA binding sites in its 3 -UTR and is regulated by miR-939 (Guo et al., 2012). Furthermore, ectopic expression of miR-939 significantly decreases iNOS protein levels in human hepatocytes, without interfering with iNOS cytokine-induced transcription (Guo et al., 2012). Thus, miR-939 acts on the iNOS 3-UTR and post-transcriptionally alters iNOS protein levels. Other iNOS regulating microRNA have also been described such as miR-146 which prevents iNOS expression in murine renal cancer RENCA cells (Perske et al., 2010). In this context miR-146 is proposed to facilitate tumour cells to evade NO-induced, macrophage-mediated, cell death (Perske et al., 2010). miR-34a is induced by p53 and up-regulated by interleukin-1␤ and in vitro silencing of miR-34a prevents IL-1␤-induced iNOS expression (Abouheif et al., 2010). Although the expression of this cellular miRNA in virus infection is currently unknown, the IL-1␤converting enzyme (ICE) and IL-1 are strongly implicated in iNOS expression in the context of inflammation (Jüttler et al., 2007), since ICE has long been known to be inhibited by virally encoded protease inhibitors such as CrmA (Komiyama et al., 1994; Ray et al., 1992). Finally, it has recently been reported that iNOS can also be regulated by miRNA-mediated control of iNOS inducing proteins, such as TGF␤-activated kinase 1 (TAK1) (Xu et al., 2013). In this scenario, mi-R155 can prevent iNOS expression by targeting TAK1-binding protein 2 otherwise known as TAB2 (Xu et al., 2013). In an analogous manner, miR-27b influences iNOS expression by targeting KH-type splicing regulatory protein (KSRP) levels (Zhou et al., 2012b). Taken together these data show that iNOS is an IFN-stimulated anti-viral effector molecule prone to direct or indirect miRNA control. 5.6. Adenosine deaminase acting on RNA (ADAR) The adenosine deaminase acting on RNA (ADAR) (Patterson and Samuel, 1995; Patterson et al., 1995) is both constitutively expressed and IFN-inducible (George and Samuel, 1999), by virtue of an alternate proximal promoter IRSE (George and Samuel, 1991). ADAR enzymes convert adenosine to inosine in dsRNAs, where the inosine substitution is decoded as guanosine (G) during translation, and by polymerases during RNA-dependent RNA replication (Gerber and Keller, 1999). The importance of this nucleotide exchange is evident by the fact that ADARs can edit both cellular

788

L.M. Sedger / Molecular Immunology 56 (2013) 781–793

of ADAR can have extensive effects on cellular miRNA expression and function, influencing miRNA processing and generation, as well as target sequence activity and functional gene silencing. 5.7. APOBEC-family molecules

Fig. 3. (A) IFN/IFN-R signalling transcriptionally activates IFN-induced gene expression, including genes such as ADAR1. (B) ADAR1 RNA editing protein converts adenosine (A) nucleotide to inosine (I) including on RNA including pri-microRNA molecules produced from pre-miRNA by Drosha and DGCR8. (C) The A-to-I miRNA editing changes the seed sequence specificity of the processed, mature miRNA, and therefore potentially leads to alternative cellular or viral target mRNA homology and altered gene silencing through mRNA degradation or transcriptional inhibition, depending on the degree of homology with the target sequence.

and viral RNAs (Dabiri et al., 1996; Wong and Lazinski, 2002). For example, in hepatitis delta virus the small delta antigen is expressed throughout infection, but the large antigen is expressed late and required for viral particle morphogenesis, and RNA editing is required to convert the small antigen UAG stop codon to a UIG tryptophan codon (Casey and Gerin, 1995). RNA editing by ADAR can be both pro- and anti-viral, as ADARs effect measles virus, vesicular stomatitis virus, lymphocytic choriomeningitis virus and Rift Valley fever virus, hepatitis C and D, HIV and human herpes viruses including Kaposi’s sarcoma-associated herpesvirus (HHV8) and Epstein–Barr virus (EBV), replication (for reviews see George et al., 2011; Samuel, 2011). ADARs are not only important in mRNA editing, but they can also influence miRNA function. ADAR editing of miRNA within the seedsequence can selectively alter their specificity and impart miRNA regulation to genes other than the original adenosine-specific seedsequence complementary templates (Kawahara et al., 2007b) (see Fig. 3). Additionally, A-to-I miRNA editing can theoretically lead to differential mechanisms of miRNA-dependant mRNA silencing, i.e. mRNA cleavage or translational inhibition (Fabian and Sonenberg, 2012). It could also theoretically alter binding and functionality of miRNAs that enhance virus replication, such as miR-122 which binds to the 5 - and 3 HCV UTRs, shielding them form RNase degradation (Li et al., 2013a). In other words IFN-induced ADAR can change the mechanism of miRNA action on its molecular targets. In fact it has been estimated that up to 20% of miRNAs could be sensitive to adenosine-to-inosine (A-to-I) ADAR editing activity. RNA editing can also result in the blocking of Dicer pre-miRNA processing and hence ADAR also prevents miRNA biogenesis. This effect has been shown for miR-151 (Kawahara et al., 2007a). The effects of ADAR on miRNA are not restricted to cellular miRNAs, but they can also influence viral miRNAs. For instance, in Epstein Barr virus biology the EBV genome encodes at least 23 miRNA (Cai et al., 2006). Although the functions and targets of many EBV miRNA are unknown, ADAR A-to-I editing of pri-miR-BART6 in Daudi Burkitt lymphoma cells suppresses processing of the pre-miRNA which correlates with altered states of viral latency (Iizasa et al., 2010). Taken together, these findings show that IFN-induced expression

Several apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) proteins are cytidine deaminase proteins (Smith et al., 2012) and they are important restriction factors that protect against human retroviruses. APOBEC3 family molecules are inducible by innate IFNs (IFN␣ and IFN␭) (Tanaka et al., 2006; Wang et al., 2008; Zhou et al., 2009), as well as immune IFN, IFN␥ (Argyris et al., 2007). They control HIV replication in human brain microvascular endothelial cells (Argyris et al., 2007) as well as in infected monocytes, macrophages, and CD4T cells (Chiu et al., 2005; Wahl et al., 2007). Interestingly, the anti-viral activity of APOBEC3G is sometimes independent of its cytidine deaminase activity (Newman et al., 2005) and is found as an enzymatically active low-molecular-mass form or as an inactive high-molecularmass RNA-protein complex (Gallois-Montbrun et al., 2007). Thus whilst APOBEC proteins interact with RNA and RNA-associated proteins (Gallois-Montbrun et al., 2007, 2008), APOBEC3G also counteracts the inhibition of protein synthesis by microRNAs (miRNAs), including miR-10b, miR-16, miR-25, and let-7a, which results in increased expression of the miRNA-targeted gene (Huang et al., 2007). As alluded to above, this can be independent of its deaminase activity, and in fact current information suggests its activity maybe related to its ability to complex with Argonaute-2 (GalloisMontbrun et al., 2007). 5.8. IFN-stimulated gene 15 (ISG15) A review of IFN-inducible genes is incomplete without mention of IFN-stimulated gene 15 (ISG15) which is a ubiquitin-like molecule (Loeb and Haas, 1992; Narasimhan et al., 1996). The conjugation of ISG15 to proteins is termed “ISGlyation”, and involves a reversible, three-step process of activating, conjugating, and ligating ISG15 to cellular and viral proteins (for review see Skaug and Chen, 2010). Unlike ubiquitin, however, ISGlyation does not usually lead to protein degradation, but conversely to protein stability. There are now more than 150 proteins that have been described as post-transcriptionally modified by ISGlyation, many of which are IFN-inducible proteins including PKR, MxA, HuP56 and RIG-I helicase (Zhao et al., 2005). Exactly how ISG15 is anti-viral is controversial and still the topic of ongoing research. Suffice to note that ISG15 gene targeted mice are reportedly more susceptible to virus infection with influenza virus, sindbis virus, herpes simplex virus, murine ␥-herpes virus and human chickungunya virus (Lenschow et al., 2005, 2007), although noticeably not more sensitive to vesicular stomatitis virus or lymphocytic choriomeningitis virus (Osiak et al., 2005). Some viruses appear to target the ISGylation pathway either by virtue of expressing viral proteins that bind to ISG15 and blocking its interaction with other substrates (e.g. influenza B NS1) (Yuan and Krug, 2001), or by viral proteases which can deISGylate the ISG15-modified substrate (e.g. from nairoviruses, arteriviruses and the SARS coronovirus) (Frias-Staheli et al., 2007). It is unknown whether vesicular stomatitis virus and lymphocytic choriomeningitis virus specifically evade ISGylation in a similar manner. There is little information known of miRNA control of ISG15, especially in the context of virus infection. However miRNA microarray analysis has identified miR-182, miR-183, and miR-200a and b as potential regulators of the E2-ubiquitin conjugating enzyme 21E, and bioinformatics analysis also identified binding sites within the ISG15 gene (Lee et al., 2012b). Thus further research is needed to determine if these miRNA directly or indirectly control aspects of ISG15-function.

L.M. Sedger / Molecular Immunology 56 (2013) 781–793

6. Concluding comments IFNs are potently anti-viral and work synergistically with numerous IFN-regulated genes, including both protein coding and non-coding genes. Together IFNs and IFN-inducible gene products constitute the cells response to virus infection. As such, cellular miRNA are clearly integral to a cells response to IFNs and to virus infection. Similarly, virally encoded miRNA can interfere with IFN or IFN-inducible genes to regulate their expression and thus limit their function. The outcome of virus infection is therefore dependent on a fine balance of pro- and anti-viral factors, comprising IFNs, IFNinducible genes, and cellular and viral miRNA. That no miRNAs have been identified with direct activity on Mx or OAS is intriguing, but may highlight the necessity of these anti-viral effectors for cell survival. On the other hand, Mx or OAS activate RNaseL, which is itself is directly controlled by miR-29. Mx and AOS biology are therefore sensitive to downstream miRNA control. Finally, the impact of RNA editing machinery to alter miRNA sequence specificity, reveals a novel and important interaction influencing the regulation of virus replication and the final outcome of virus infection. Conflict of interest The author declares that there are no conflicts-of-interest that could be perceived as prejudicing the interpretation of the research reported. Acknowledgements The author thanks Dr Nham Tran (University of Technology Sydney, UTS) for thoughtful comments on the manuscript. LMS is an Adjunct Research Fellow in Dr Ranasinghe’s laboratory, Department of Immunology, John Curtin School of Medical Research, Australian National University. She is also an Honorary Senior Lecturer in Microbiology in Faculty of Science at The University of Technology Sydney where she lectures in Medical Virology within the MBBS programme at the University of Notre Dame Australia. References Abdelmohsen, K., Srikantan, S., Kuwano, Y., Gorospe, M., 2008. miR-519 reduces cell proliferation by lowering RNA-binding protein HuR levels. Proceedings of the National Academy of Sciences of the United States of America 105, 20297–20302. Abouheif, M.M., Nakasa, T., Shibuya, H., Niimoto, T., Kongcharoensombat, W., Ochi, M., 2010. Silencing microRNA-34a inhibits chondrocyte apoptosis in a rat osteoarthritis model in vitro. Rheumatology (Oxford) 49, 2054–2060. Aebi, M., Fäh, J., Hurt, N., Samuel, C.E., Thomis, D., Bazzigher, L., Pavlovic, J., Haller, O., Staeheli, P., 1989. cDNA structures and regulation of two interferon-induced human Mx proteins. Molecular Cell Biology 9, 5062–5072. ´ Z., Merlin, G., 1988. Molecular cloning and expression of the Aguet, M., Dembic, human interferon-␥ receptor. Cell 55, 273–280. Ank, N., West, H., Bartholdy, C., Eriksson, K., Thomsen, A.R., Paludan, S.R., 2006. Lambda interferon (IFN-␭), a type III IFN, is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo. Journal of Virology 80, 4501–4509. Argyris, E.G., Acheampong, E., Wang, F., Huang, J., Chen, K., Mukhtar, M., Zhang, H., 2007. The interferon-induced expression of APOBEC3G in human blood-brain barrier exerts a potent intrinsic immunity to block HIV-1 entry to central nervous system. Virology 367, 440–451. Arnheiter, H., Haller, O., 1988. Antiviral state against influenza virus neutralized by microinjection of antibodies to interferon-induced Mx proteins. EMBO Journal 7, 1315–1320. Arnheiter, H., Skuntz, S., Noteborn, M., Chang, S., Meier, E., 1990. Transgenic mice with intracellular immunity to influenza virus. Cell 62, 51–61. Asselah, T., Estrabaud, E., Bieche, I., Lapalus, M., De Muynck, S., Vidaud, M., Saadoun, D., Soumelis, V., Marcellin, P., 2010. Hepatitis C: viral and host factors associated with non-response to pegylated interferon plus ribavirin. Liver International 30, 1259–1269. Balachandran, S., Roberts, P.C., Brown, L.E., Truong, H., Pattnaik, A.K., Archer, D.R., Barber, G.N., 2000. Essential role for the dsRNA-dependent protein kinase PKR in innate immunity to viral infection. Immunity 13, 129–141. Bandi, P., Pagliaccetti, N.E., Robek, M.D., 2010. Inhibition of type III interferon activity by orthopoxvirus immunomodulatory proteins. Journal of Interferon & Cytokine Research 30, 123–134.

789

Banerjee, A., Schambach, F., DeJong, C.S., Hammond, S.M., Reiner, S.L., 2010. MicroRNA-155 inhibits IFN-gamma signaling in CD4+ T cells. European Journal of Immunology 40, 225–231. Basler, C.F., Mikulasova, A., Martinez-Sobrido, L., Paragas, J., Mühlberger, E., Bray, M., Klenk, H.D., Palese, P., García-Sastre, A., 2003. The Ebola virus VP35 protein inhibits activation of interferon regulatory factor 3. Journal of Virology 77, 7945–7956. Basler, C.F., Wang, X., Mühlberger, E., Volchkov, V., Paragas, J., Klenk, H.D., GarcíaSastre, A., Palese, P., 2000. The Ebola virus VP35 protein functions as a type I IFN antagonist. Proceedings of the National Academy of Sciences of the United States of America 97, 12289–12294. Beilharz, T.H., Humphreys, D.T., Clancy, J.L., Thermann, R., Martin, D.I., Hentze, M.W., Preiss, T., 2009. microRNA-mediated messenger RNA deadenylation contributes to translational repression in mammalian cells. PLoS ONE 4, e6783. Bell, B.D., Kitajima, M., Larson, R.P., Stoklasek, T.A., Dang, K., Sakamoto, K., Wagner, K.U., Reizis, B., Hennighausen, L., Ziegler, S.F., 2011. The transcription factor STAT5 is critical in dendritic cells for the development of TH2 but not TH1 responses. Nature Immunology 14, 364–371. Breving, K., Esquela-Kerscher, A., 2010. The complexities of microRNA regulation: mirandering around the rules. International Journal of Biochemistry & Cell Biology 42, 1316–1329. Brierley, M.M., Fish, E.N., 2005. Stats: multifaceted regulators of transcription. Journal of Interferon & Cytokine Research 25, 733–744. Brueckner, B., Stresemann, C., Kuner, R., Mund, C., Musch, T., Meister, M., Sültmann, H., Lyko, F., 2007. The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function. Cancer Research 67, 1419–1423. Cai, X., Schäfer, A., Lu, S., Bilello, J.P., Desrosiers, R.C., Edwards, R., Raab-Traub, N., Cullen, B.R., 2006. Epstein–Barr virus microRNAs are evolutionarily conserved and differentially expressed. PLoS Pathogens 2, e23. Cárdenas, W.B., Loo, Y.M., Gale, M.J., Hartman, A.L., Kimberlin, C.R., Martínez-Sobrido, L., Saphire, E.O., Basler, C.F., 2006. Ebola virus VP35 protein binds doublestranded RNA and inhibits alpha/beta interferon production induced by RIG-I signaling. Journal of Virology 80, 5168–5178. Casey, J.L., Gerin, J.L., 1995. Hepatitis D virus RNA editing: specific modification of adenosine in the antigenomic RNA. Journal of Virology 69, 7593–7600. Celada, A., Allen, R., Esparza, I., Gray, P.W., Schreiber, R.D., 1985. Demonstration and partial characterization of the interferon-gamma receptor on human mononuclear phagocytes. Journal of Clinical Investigation 76, 2196–2205. Chakrabarti, A., Jha, B.K., Silverman, R.H., 2011. New insights into the role of RNaseL in innate immunity. Journal of Interferon & Cytokine Research 31, 49–57. Chen, H.M., Tanaka, N., Mitani, Y., Oda, E., Nozawa, H., Chen, J.Z., Yanai, H., Negishi, H., Choi, M.K., Iwasaki, T., Yamamoto, H., Taniguchi, T., Takaoka, A., 2009. Critical role for constitutive type I interferon signaling in the prevention of cellular transformation. Cancer Science 100, 449–456. Chiu, Y.L., Soros, V.B., Kreisberg, J.F., Stopak, K., Yonemoto, W., Greene, W., 2005. Cellular APOBEC3G restricts HIV-1 infection in resting CD4+ T cells. Nature 435, 108–114. Coccia, E.M., Severa, M., Giacomini, E., Monneron, D., Remoli, M.E., Julkunen, I., Cella, M., Lande, R., Uzé, G., 2004. Viral infection and Toll-like receptor agonists induce a differential expression of type I and lambda interferons in human plasmacytoid and monocyte-derived dendritic cells. European Journal of Immunology 34, 796–805. Cosman, D., Müllberg, J., Sutherland, C.L., Chin, W., Armitage, R., Fanslow, W., Kubin, M., Chalupny, N.J., 2001. ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 14, 123–133. Dabiri, G.A., Lai, F., Drakas, R.A., Nishikura, K., 1996. Editing of the GLuR-B ion channel RNA in vitro by recombinant double-stranded RNA adenosine deaminase. EMBO Journal 15, 34–45. Darnell Jr., J.E., Kerr, I.M., Stark, G.R., 1994. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264, 1415–1421. De Marchis, M.L., Ballarino, M., Salvatori, B., Puzzolo, M.C., Bozzoni, I., Fatica, A., 2009. A new molecular network comprising PU.1, interferon regulatory factor proteins and miR-342 stimulates ATRA-mediated granulocytic differentiation of acute promyelocytic leukemia cells. Leukemia 23, 856–862. de Weerd, N.A., Nguyen, T., 2012. The interferons and their receptors – distribution and regulation. Immunology and Cell Biology 90, 483–491. De Zoysa, M., Kang, H.S., Song, Y.B., Jee, Y., Lee, Y.D., Lee, J., 2007. First report of invertebrate Mx: cloning, characterization and expression analysis of Mx cDNA in disk abalone (Haliotis discus discus). Fish and Shellfish Immunology 23, 86–96. Denli, A.M., Tops, B.B., Plasterk, R.H., Ketting, R.F., Hannon, G.J., 2005. Processing of primary microRNAs by the Microprocessor complex. Nature 432, 231–235. Diamond, M.S., Kinder, M., Matsushita, H., Mashayekhi, M., Dunn, G.P., Archambault, J.M., Lee, H., Arthur, C.D., White, J.M., Kalinke, U., Murphy, K.M., Schreiber, R.D., 2011. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. Journal of Experimental Medicine 208, 1989–2003. Dimitriou, I.D., Clemenza, L., Scotter, A.J., Chen, G., Guerra, F.M., Rottapel, R., 2008. Putting out the fire: coordinated suppression of the innate and adaptive immune systems by SOCS1 and SOCS3 proteins. Immunological Reviews 224, 265–283. Ding, S.W., Lu, R., 2011. Virus-derived siRNAs and piRNAs in immunity and pathogenesis. Current Opinion in Virology 1, 533–544. Donnelly, R.P., Kotenko, S.V., 2010. Interferon-lambda: a new addition to an old family. Journal of Interferon & Cytokine Research 30, 555–564. Dorin, D., Bonnet, M.C., Bannwarth, S., Gatignol, A., Meurs, E.F., Vaquero, C., 2003. The TAR RNA-binding protein, TRBP, stimulates the expression of TAR-containing

790

L.M. Sedger / Molecular Immunology 56 (2013) 781–793

RNAs in vitro and in vivo independently of its ability to inhibit PKR. Journal of Biological Chemistry 278, 4440–4448. Dudda, J.C., Salaun, B., Ji, Y., Palmer, D.C., Monnot, G.C., Merck, E., Boudousquie, C., Utzschneider, D.T., Escobar, T.M., Perret, R., Muljo, S.A., Hebeisen, M., Rufer, N., Zehn, D., Donda, A., Restifo, N.P., Held, W., Gattinoni, L., Romero, P., 2013. MicroRNA-155 is required for effector CD8+ T cell responses to virus infection and cancer. Immunity 38, 742–753. Dumoutier, L., Tounsi, A., Michiels, T., Sommereyns, C., Kotenko, S.V., Renauld, J.C., 2004. Role of the interleukin (IL)-28 receptor tyrosine residues for antiviral and antiproliferative activity of IL-29/interferon-␭1: similarities with type I interferon signaling. Journal of Biological Chemistry 279, 32269–32274. Durbin, J.E., Hackenmiller, R., Simon, M.C., Levy, D.E., 1996. Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell 84, 443–450. El Awady, M.K., Anany, M.A., Esmat, G., Zayed, N., Tabll, A.A., Helmy, A., El Zayady, A.R., Abdalla, M.S., Sharada, H.M., El Raziky, M., El Akel, W., Abdalla, S., Bader El Din, N.G., 2011. Single nucleotide polymorphism at exon 7 splice acceptor site of OAS1 gene determines response of hepatitis C virus patients to interferon therapy. Journal of Gastroenterology & Hepatology 26, 843–850. Englebienne, P., Verhas, M., Herst, C.V., De Meirleir, K., 2003. Type I interferons induce proteins susceptible to act as thyroid receptor (TR) corepressors and to signal the TR for destruction by the proteasome: possible etiology for unexplained chronic fatigue. Medical Hypotheses 60, 175–180. Fabian, M.R., Sonenberg, N., 2012. The mechanics of miRNA-mediated gene silencing: a look under the hood of miRISC. Nature Structural & Molecular Biology 19, 586–593. Feng, Z., Cerveny, M., Yan, Z., He, B., 2007. The VP35 protein of Ebola virus inhibits the antiviral effect mediated by double-stranded RNA-dependent protein kinase PKR. Journal of Virology 81, 182–192. Fensterl, V., Sen, G.C., 2009. Interferons and viral infections. BioFactors 35, 14–20. Floyd-Smith, G., Slattery, E., Lengyel, P., 1981. Interferon action: RNA cleavage pattern of a (2 -5 ) oligoadenylate-dependent endonuclease. Science 212, 1030–1032. Frias-Staheli, N., Giannakopoulos, N.V., Kikkert, M., Taylor, S.L., Bridgen, A., Paragas, J., Richt, J.A., Rowland, R.R., Schmaljohn, C.S., Lenschow, D.J., Snijder, E.J., GarcíaSastre, A., Virgin, H.W., 2007. Ovarian tumor domain-containing viral proteases evade ubiquitin- and ISG15-dependent innate immune responses. Cell Host & Microbe 2, 404–416. Fuertes, M.B., Kacha, A.K., Kline, J., Woo, S.R., Kranz, D.M., Murphy, K.M., Gajewski, T.F., 2011. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8␣+ dendritic cells. Journal of Experimental Medicine 208, 2005–2016. ˜ M., Byers, H.L., Gallois-Montbrun, S., Holmes, R.K., Swanson, C.M., Fernández-Ocana, Ward, M.A., Malim, M.H., 2008. Comparison of cellular ribonucleoprotein complexes associated with the APOBEC3F and APOBEC3G antiviral proteins. Journal of Virology 82, 5636–5642. Gallois-Montbrun, S., Kramer, B., Swanson, C.M., Byers, H., Lynham, S., Ward, M., Malim, M.H., 2007. Antiviral protein APOBEC3G localizes to ribonucleoprotein complexes found in P bodies and stress granules. Journal of Virology 81, 2165–2178. Gao, J., Morrison, D.C., Parmely, T.J., Russell, S.W., Murphy, W.J., 1997. An interferon␥-activated site (GAS) is necessary for full expression of the mouse iNOS gene in response to interferon-gamma and lipopolysaccharide. Journal of Biological Chemistry 272, 1226–1230. Garber, E.A., Chute, H.T., Condra, J.H., Gotlib, L., Colonno, R.J., Smith, R.G., 1991. Avian cells expressing the murine Mx1 protein are resistant to influenza virus infection. Virology 180, 754–762. Gatignol, A., Buckler-White, A., Berkhout, B., Jeang, K.T., 1991. Characterization of a human TAR RNA-binding protein that activates the HIV-1 LTR. Science 251, 1597–1600. Ge, D., Fellay, J., Thompson, A.J., Simon, J.S., Shianna, K.V., Urban, T.J., Heinzen, E.L., Qiu, P., Bertelsen, A.H., Muir, A.J., Sulkowski, M., McHutchison, J.G., Goldstein, D.B., 2009. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461, 399–401. George, C.X., Gan, Z., Liu, Y., Samuel, C.E., 2011. Adenosine deaminases acting on RNA, RNA editing, and interferon action. Journal of Interferon & Cytokine Research 31, 99–117. George, C.X., Samuel, C.E., 1991. Characterization of the 5 -flanking region of the human RNA-specific adenosine deaminase ADAR1 gene and identification of an interferon-inducible ADAR1 promoter. Gene 229, 203–213. George, C.X., Samuel, C.E., 1999. Human RNA-specific adenosine deaminase ADAR1 transcripts possess alternative exon 1 structures that initiate from different promoters, one constitutively active and the other interferon inducible. Proceedings of the National Academy of Sciences of the United States of America 96, 4621–4626. Gerber, A.P., Keller, W., 1999. An adenosine deaminase that generates inosine at the wobble position of tRNAs. Science 286, 1146–1149. Gil, J., Esteban, M., 2000. The interferon-induced protein kinase (PKR), triggers apoptosis through FADD-mediated activation of caspase 8 in a manner independent of Fas and TNF-␣ receptors. Oncogene 19, 3665–3674. Goetschy, J.F., Zeller, H., Content, J., Horisberger, M.A., 1989. Regulation of the interferon-inducible IFI-78K gene, the human equivalent of the murine Mx gene, by interferons, double-stranded RNA, certain cytokines, and viruses. Journal of Virology 63, 2616–2622. Gracias, D.T., Stelekati, E., Hope, J.L., Boesteanu, A.C., Doering, T.A., Norton, J., Mueller, Y.M., Fraietta, J.A., Wherry, E.J., Turner, M., Katsikis, P.D., 2013. The microRNA

miR-155 controls CD8+ T cell responses by regulating interferon signaling. Nature Immunology 14, 593–602. Gregersen, L.H., Jacobsen, A.B., Frankel, L.B., Wen, J., Krogh, A., Lund, A.H., 2010. MicroRNA-145 targets YES and STAT1 in colon cancer cells. PLoS ONE 5, e8836. Griffiths-Jones, S., Saini, H.K., van Dongen, S., Enright, A.J., 2008. miRBase: tools for microRNA genomics. Nucleic Acids Research 36, D154–D158 (Database issue). Groh, V., Rhinehart, R., Randolph-Habecker, J., Topp, M.S., Riddell, S.R., Spies, T., 2001. Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nature Immunology 2, 255–260. Gu, L., Song, G., Chen, L., Nie, Z., He, B., Pan, Y., Xu, Y., Li, R., Gao, T., Cho, W.C., Wang, S., 2013. Inhibition of miR-21 induces biological and behavioral alterations in diffuse large B-cell lymphoma. Acta Haematologica 130, 87–94. Guo, Z., Shao, L., Zheng, L., Du, Q., Li, P., John, B., Geller, D.A., 2012. miRNA-939 regulates human inducible nitric oxide synthase posttranscriptional gene expression in human hepatocytes. Proceedings of the National Academy of Sciences of the United States of America 109, 5826–5831. Gururajan, M., Haga, C.L., Das, S., Leu, C.M., Hodson, D., Josson, S., Turner, M., Cooper, M.D., 2010. MicroRNA 125b inhibition of B cell differentiation in germinal centers. International Immunology 22, 583–592. Haase, A.D., Jaskiewicz, L., Zhang, H., Lainé, S., Sack, R., Gatignol, A., Filipowicz, W., 2005. TRBP, a regulator of cellular PKR and HIV-1 virus expression, interacts with dicer and functions in RNA silencing. EMBO Reports 6, 961–967. Haller, O., Staeheli, P., Kochs, G., 2009. Protective role of interferon-induced Mx GTPases against influenza viruses. Revue scientifique et technique 28, 219–231. Haller, O., Stertz, S., Kochs, G., 2007. The Mx GTPase family of interferon-induced antiviral proteins. Microbes and Infection 9, 1636–1643. Hambleton, S., Goodbourn, S., Young, D.F., Dickinson, P., Mohamad, S.M., Valappil, M., McGovern, N., Cant, A.J., Hackett, S.J., Ghazal, P., Morgan, N.V., Randall, R.E., 2013. STAT2 deficiency and susceptibility to viral illness in humans. Proceedings of the National Academy of Sciences of the United States of America 110, 3053–3058. He, J., Yue, Y., Dong, C., Xiong, S., 2013. MiR-21 confers resistance against CVB3-induced myocarditis by inhibiting PDCD4-mediated apoptosis. Clinical & Investigative Medicine 36, E103. Hilleman, M.R., 1970. Double-stranded RNAs (poly I:C) in the prevention of viral infections. Archives of Internal Medicine 126, 109–124. Holzinger, D., Jorns, C., Stertz, S., Boisson-Dupuis, S., Thimme, R., Weidmann, M., Casanova, J.L., Haller, O., Kochs, G., 2007. Induction of MxA gene expression by influenza A virus requires type I or type III interferon signaling. Journal of Virology 81, 7776–7785. Horisberger, M.A., McMaster, G.K., Zeller, H., Wathelet, M.G., Dellis, J., Content, J., 1990. Cloning and sequence analyses of cDNAs for interferon- and virus-induced human Mx proteins reveal that they contain putative guanine nucleotidebinding sites: functional study of the corresponding gene promoter. Journal of Virology 64, 1171–1181. Horisberger, M.A., Wathelet, M., Szpirer, J., Szpirer, C., Islam, Q., Levan, G., Huez, G., Content, J., 1988. cDNA cloning and assignment to chromosome 21 of IFI-78K gene, the human equivalent of murine Mx gene. Somatic Cell and Molecular Genetics 14, 123–131. Hovanessian, A.G., 2007. On the discovery of interferon-inducible, double-stranded RNA activated enzymes: the 2 -5 oligoadenylate synthetases and the protein kinase PKR. Cytokine & Growth Factor Reviews 18, 351–361. Hovanessian, A.G., Justesen, J., 2007. The human 2 -5 oligoadenylate synthetase family: unique interferon-inducible enzymes catalyzing 2 -5 instead of 3 -5 phosphodiester bond formation. Biochimie 89, 779–788. Hovnanian, A., Rebouillat, D., Levy, E.R., Mattei, M.G., Hovanessian, A.G., 1999. The human 2’,5’-oligoadenylate synthetase-like gene (OASL) encoding the interferon-induced 56-kDa protein maps to chromosome 12q24.2 in the proximity of the 2’,5’-OAS locus. Genomics 56, 362–363. Huang, J., Liang, Z., Yang, B., Tian, H., Ma, J., Zhang, H., 2007. Derepression of microRNA-mediated protein translation inhibition by apolipoprotein B mRNAediting enzyme catalytic polypeptide-like 3G (APOBEC3G) and its family members. Journal of Biological Chemistry 282, 33632–33640. Huang, Y., Lei, Y., Zhang, H., Hou, L., Zhang, M., Dayton, A.I., 2011. MicroRNA regulation of STAT4 protein expression: rapid and sensitive modulation of IL-12 signaling in human natural killer cells. Blood 118, 6793–6802. Hug, H., Costas, M., Staeheli, P., Aebi, M., Weissmann, C., 1988. Organization of the murine Mx gene and characterization of its interferon- and virus-inducible promoter. Molecular Cell Biology 8, 3065–3079. Humphreys, D.T., Westman, B.J., Martin, D.I., Preiss, T., 2005. MicroRNAs control translation initiation by inhibiting eukaryotic initiation factor 4E/cap and poly(A) tail function. Proceedings of the National Academy of Sciences of the United States of America 102, 16961–16966. Hutvagner, G., 2005. Small RNA asymmetry in RNAi: function in RISC assembly and gene regulation. FEBS Letters 579, 5850–5857. Hutvágner, G., Zamore, P.D., 2002. A microRNA in a multiple-turnover RNAi enzyme complex. Science 297, 2056–2060. Iizasa, H., Wulff, B.E., Alla, N.R., Maragkakis, M., Megraw, M., Hatzigeorgiou, A., Iwakiri, D., Takada, K., Wiedmer, A., Showe, L., Lieberman, P., Nishikura, K., 2010. Editing of Epstein–Barr virus-encoded BART6 microRNAs controls their dicer targeting and consequently affects viral latency. Journal of Biological Chemistry 285, 33358–33370. Isaacs, A., Lindenmann, J., 1957. Virus interferance, I. The interferon. Proceedings of the Royal Society of London Series B: Biological Sciences 147, 258–267. Ishibashi, M., Wakita, T., Esumi, M., 2010. 2 ,5 -Oligoadenylate synthetase-like gene highly induced by hepatitis C virus infection in human liver is inhibitory to viral

L.M. Sedger / Molecular Immunology 56 (2013) 781–793 replication in vitro. Biochemical and Biophysical Research Communications 392, 397–402. Ito, T., Yang, M., May, W.S., 1999. RAX, a cellular activator for doublestranded RNAdependent protein kinase during stress signaling. Journal of Biological Chemistry 274, 15427–15432. Janowski, B.A., Younger, S.T., Hardy, D.B., Ram, R., Huffman, K.E., Corey, D.R., 2007. Activating gene expression in mammalian cells with promoter-targeted duplex RNAs. Nature Chemical Biology 3, 166–173. Jensen, S., Thomsen, A.R., 2012. Sensing of RNA viruses: a review of innate immune receptors involved in recognizing RNA virus invasion. Journal of Virology 86, 2900–2910. Jeon, S.H., Lee, K., Lee, K.S., Kunkeaw, N., Johnson, B.H., Holthauzen, L.M., Gong, B., Leelayuwat, C., Lee, Y.S., 2012. Characterization of the direct physical interaction of nc886, a cellular non-coding RNA, and PKR. FEBS Letters 586, 3477–3484. Jin, H.K., Takada, A., Kon, Y., Haller, O., Watanabe, T., 1999. Identification of the murine Mx2 gene: interferon-induced expression of the Mx2 protein from the feral mouse gene confers resistance to vesicular stomatitis virus. Journal of Virology 73, 4925–4930. Joshi, A.R., Sarkar, F.H., Gupta, S.L., 1982. Interferon receptors, cross-linking of human leukocyte interferon alpha-2 to its receptor on human cells. Journal of Biological Chemistry 257, 13884–13887. Jüttler, E., Bonmann, E., Spranger, M., Kolb-Bachofen, V., Suschek, C.V., 2007. A novel role of interleukin-1-converting enzyme in cytokine-mediated inducible nitric oxide synthase gene expression: Implications for neuroinflammatory diseases. Molecular and Cellular Neuroscience 34, 612–620. Kajaste-Rudnitski, A., Mashimo, T., Frenkiel, M.P., Guénet, J.L., Lucas, M., Desprès, P., 2006. The 2 ,5 -oligoadenylate synthetase 1b is a potent inhibitor of West Nile virus replication inside infected cells. Journal of Biological Chemistry 281, 4624–4637. Kapinas, K., Delany, A.M., 2011. MicroRNA biogenesis and regulation of bone remodeling. Arthritis Research & Therapy 13 (3), 220. Karupiah, G., Blanden, R.V., Ramshaw, I.A., 1990. Interferon gamma is involved in the recovery of athymic nude mice from recombinant vaccinia virus/interleukin 2 infection. J. Exp. Med. 172 (5), 1495–1503. Karupiah, G., Xie, Q.W., Buller, R.M., Nathan, C., Duarte, C., MacMicking, J.D., 1993. Inhibition of viral replication by interferon-gamma induced nitric oxide synthase. Science 261, 1445–1448. Kato, H., Takeuchi, O., Sato, S., Yoneyama, M., Yamamoto, M., Matsui, K., Uematsu, S., Jung, A., Kawai, T., Ishii, K.J., Yamaguchi, O., Otsu, K., Tsujimura, T., Koh, C.S., Reis e Sousa, C., Matsuura, Y., Fujita, T., Akira, S., 2006. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441, 101–105. Kawahara, Y., Zinshteyn, B., Chendrimada, T.P., Shiekhattar, R., Nishikura, K., 2007a. RNA editing of the microRNA-151 precursor blocks cleavage by the Dicer-TRBP complex. EMBO Journal 8, 763–769. Kawahara, Y., Zinshteyn, B., Sethupathy, P., Iizasa, H., Hatzigeorgiou, A.G., Nishikura, K., 2007b. Redirection of silencing targets by adenosine-to-inosine editing of miRNAs. Science 315, 1137–1140. Kim, V.N., Nam, J.W., 2006. Genomics of microRNA. Trends in Genetics 22, 165–173. Knapp, S., Yee, L.J., Frodsham, A.J., Hennig, B.J., Hellier, S., Zhang, L., Wright, M., Chiaramonte, M., Graves, M., Thomas, H.C., Hill, A.V., Thursz, M.R., 2003. Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infection: roles of MxA, OAS-1 and PKR. Genes & Immunity 4, 411–419. Kochs, G., Haller, O., 1999a. GTP-bound human MxA protein interacts with the nucleocapsids of Thogoto virus Orthomyxoviridae). Journal of Biological Chemistry 274, 4370–4376. Kochs, G., Haller, O., 1999b. Interferon-induced human MxA GTPase blocks nuclear import of Thogoto virus nucleocapsids. Proceedings of the National Academy of Sciences of the United States of America 96, 2082–2086. Kohanbash, G., Okada, H., 2012. MicroRNAs and STAT interplay. Seminars in Cancer Biology 22, 70–75. Kok, K.H., Lui, P.Y., Ng, M.H., Siu, K.L., Au, S.W., Jin, D.Y., 2011. The double-stranded RNA-binding protein PACT functions as a cellular activator of RIG-I to facilitate innate antiviral response. Cell Host & Microbe 9, 299–309. Komiyama, T., Ray, C.A., Pickup, D.J., Howard, A.D., Thornberry, N.A., Peterson, E.P., Salvesen, G., 1994. Inhibition of interleukin-1 beta converting enzyme by the cowpox virus serpin CrmA: an example of cross-class inhibition. Journal of Biological Chemistry 269, 19331–19337. Kotenko, S.V., Gallagher, G., Baurin, V.V., Lewis-Antes, A., Shen, M., Shah, N.K., Langer, J.A., Sheikh, F., Dickensheets, H., Donnelly, R.P., 2003. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nature Immunology 4, 69–77. Kutty, R.K., Nagineni, C.N., Samuel, W., Vijayasarathy, C., Hooks, J.J., Redmond, T.M., 2010. Inflammatory cytokines regulate microRNA-155 expression in human retinal pigment epithelial cells by activating JAK/STAT pathway. Biochemical and Biophysical Research Communications 402, 390–395. Kwon, Y.C., Kang, J.I., Hwang, S.B., Ahn, B.Y., 2013. The ribonuclease L-dependent antiviral roles of human 2 ,5 -oligoadenylate synthetase family members against hepatitis C virus. FEBS Letters 587, 156–164. Lagos-Quintana, M., Rauhut, R., Lendeckel, W., Tuschl, T., 2001. Identification of novel genes coding for small expressed RNAs. Science 294, 853–858. Lai, E.C., 2002. Micro RNAs are complementary to 3 UTR sequence motifs that mediate negative post-transcriptional regulation. Nature Genetics 30, 363–364. Langland, J.O., Cameron, J.M., Heck, M.C., Jancovich, J.K., Jacobs, B.L., 2006. Inhibition of PKR by RNA and DNA viruses. Virus Research 199, 100–110. Lau, N.C., Lim, L.P., Weinstein, E.G., Bartel, D.P., 2001. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 294, 858–862.

791

Lecellier, C.H., Dunoyer, P., Arar, K., Lehmann-Che, J., Eyquem, S., Himber, C., Saïb, A., Voinnet, O., 2005. A cellular microRNA mediates antiviral defense in human cells. Science 308, 557–560. Lee, K., Kunkeaw, N., Jeon, S.H., Lee, I., Johnson, B.H., Kang, G.Y., Bang, J.Y., Park, H.S., Leelayuwat, C., Lee, Y.S., 2011. Precursor miR-886, a novel noncoding RNA repressed in cancer, associates with PKR and modulates its activity. RNA 17, 1076–1089. Lee, R.C., Ambros, V., 2001. An extensive class of small RNAs in Caenorhabditis elegans. Science 294, 862–864. Lee, T.Y., Ezelle, H.J., Venkataraman, T., Lapidus, R.G., Scheibner, K.A., Hassel, B.A., 2012a. Regulation of human RNase-L by the miR-29 family reveals a novel oncogenic role in chronic myelogenous leukemia. Journal of Interferon & Cytokine Research 33, 34–42. Lee, Y., Ahn, C., Han, J., Choi, H., Kim, J., Yim, J., Lee, J., Provost, P., Rådmark, O., Kim, S., Kim, V.N., 2003. The nuclear RNase III Drosha initiates microRNA processing. Nature 425, 415–419. Lee, Y., Jeon, K., Lee, J.T., Kim, S., Kim, V.N., 2002. MicroRNA maturation: stepwise processing and subcellular localization. EMBO Journal 21, 4663–4670. Lee, Y.J., Johnson, K.R., Hallenbeck, J.M., 2012b. Global protein conjugation by ubiquitin-like-modifiers during ischemic stress is regulated by microRNAs and confers robust tolerance to ischemia. PLoS ONE 7, e47787. Lenschow, D.J., Giannakopoulos, N.V., Gunn, L.J., Johnston, C., O’Guin, A.K., Schmidt, R.E., Levine, B., Virgin, H.W., 2005. Identification of interferon-stimulated gene 15 as an antiviral molecule during Sindbis virus infection in vivo. Journal of Virology 79, 13974–13983. Lenschow, D.J., Lai, C., Frias-Staheli, N., Giannakopoulos, N.V., Lutz, A., Wolff, T., Osiak, A., Levine, B., Schmidt, R.E., García-Sastre, A., Leib, D.A., Pekosz, A., Knobeloch, K.P., Horak, I., Virgin, H.W., 2007. IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses. Proceedings of the National Academy of Sciences of the United States of America 104, 1371–1376. Levy, D.E., Darnell, J.E.J., 2002. STATs: transcriptional control and biological impact. Nature Reviews Molecular Cell Biology 3, 651–662. Lewis, B.P., Burge, C.B., Bartel, D.P., 2005. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20. Li, C.Z., Kato, N., Chang, J.H., Muroyama, R., Shao, R.X., Dharel, N., Sermsathanasawadi, R., Kawabe, T., Omata, M., 2009. Polymorphism of OAS-1 determines liver fibrosis progression in hepatitis C by reduced ability to inhibit viral replication. Liver International 29, 1413–1421. Li, L.C., Okino, S.T., Zhao, H., Pookot, D., Place, R.F., Urakami, S., Enokida, H., Dahiya, R., 2007a. Small dsRNAs induce transcriptional activation in human cells. Proceedings of the National Academy of Sciences of the United States of America 103, 17337–17342. Li, W.X., Li, H., Lu, R., Li, F., Dus, M., Atkinson, P., Brydon, E.W., Johnson, K.L., GarcíaSastre, A., Ball, L.A., Palese, P., Ding, S.W., 2004. Interferon antagonist proteins of influenza and vaccinia viruses are suppressors of RNA silencing. Proceedings of the National Academy of Sciences of the United States of America 101, 1350–1355. Li, X.L., Andersen, J.B., Ezelle, H.J., Wilson, G.M., Hassel, B.A., 2007b. Posttranscriptional regulation of RNase-L expression is mediated by the 3 -untranslated region of its mRNA. Journal of Biological Chemistry 282, 7950–7960. Li, Y., Fan, X., He, X., Sun, H., Zou, Z., Yuan, H., Xu, H., Wang, C., Shi, X., 2012. MicroRNA466l inhibits antiviral innate immune response by targeting interferon-alpha. Cellular & Molecular Immunology 9, 497–502. Li, Y., Masaki, T., Yamane, D., McGivern, D.R., Lemon, S.M., 2013a. Competing and noncompeting activities of miR-122 and the 5 exonuclease Xrn1 in regulation of hepatitis C virus replication. Proceedings of the National Academy of Sciences of the United States of America 110, 1881–1886. Li, Y., Xie, J., Xu, X., Wang, J., Ao, F., Wan, Y., Zhu, Y., 2013b. MicroRNA-548 downregulates host antiviral response via direct targeting of IFN-␭1. Protein & Cell 4, 130–141. Lin, R.J., Yu, H.P., Chang, B.L., Tang, W.C., Liao, C.L., Lin, Y.L., 2009. Distinct antiviral roles for human 2 ,5 -oligoadenylate synthetase family members against dengue virus infection. Journal of Immunology 183, 8035–8043. Lindenmann, J., 1962. Resistance of mice to mouse-adapted influenza A virus. Virology 16, 203–204. Loeb, K.R., Haas, A.L., 1992. The interferon-inducible 15-kDa ubiquitin homolog conjugates to intracellular proteins. Journal of Biological Chemistry 267, 7806–7813. Lu, C., Huang, X., Zhang, X., Roensch, K., Cao, Q., Nakayama, K.I., Blazar, B.R., Zeng, Y., Zhou, X., 2011. miR-221 and miR-155 regulate human dendritic cell development, apoptosis, and IL-12 production through targeting of p27kip1, KPC1, and SOCS-1. Blood 117, 4293–4303. Lv, L., Huang, F., Mao, H., Li, M., Li, X., Yang, M., Yu, X., 2013. MicroRNA-21 is overexpressed in renal cell carcinoma. International Journal of Biological Markers 28, e201–e207. Ma, T., Jiang, H., Gao, Y., Zhao, Y., Dai, L., Xiong, Q., Xu, Y., Zhao, Z., Zhang, J., 2011. Microarray analysis of differentially expressed microRNAs in non-regressed and regressed bovine corpus luteum tissue; microRNA-378 may suppress luteal cell apoptosis by targeting the interferon gamma receptor 1 gene. Journal of Applied Genetics 52, 481–486. Marié, I., Svab, J., Hovanessian, A.G., 1990. The binding of the 69- and 100-kD forms of 2’,5’-oligoadenylate synthetase to different polynucleotides. Journal of Interferon Res. 10, 571–578.

792

L.M. Sedger / Molecular Immunology 56 (2013) 781–793

Mashimo, T., Glaser, P., Lucas, Simon-Chazottes, D., Ceccaldi, P.E., Montagutelli, X., Despres, P., Guenet, J.L., 2003. Structural and functional genomics and evolutionary relationships in the cluster of genes encoding murine 2’,5’-oligoadenylate synthetases. Genomics 82, 537–552. Meager, A., Visvalingam, K., Dilger, P., Bryan, D., Wadhwa, M., 2005. Biological activity of interleukins-28 and -29: comparison with type I interferons. Cytokine 31, 109–118. Melamed, Z., Levy, A., Ashwal-Fluss, R., Lev-Maor, G., Mekahel, K., Atias, N., Gilad, S., Sharan, R., Levy, C., Kadener, S., Ast, G., 2013. Alternative splicing regulates biogenesis of miRNAs located across exon–intron junctions. Molecular Cell 50, 869–881. Melchjorsen, J., Kristiansen, H., Christiansen, R., Rintahaka, J., Matikainen, S., Paludan, S.R., Hartmann, R., 2009. Differential regulation of the OASL and OAS1 genes in response to viral infections. Journal of Interferon & Cytokine Research 29, 199–207. Meraz, M.A., White, J.M., Sheehan, K.C., Bach, E.A., Rodig, S.J., Dighe, A.S., Kaplan, D.H., Riley, J.K., Greenlund, A.C., Campbell, D., Carver-Moore, K., DuBois, R.N., Clark, R., Aguet, M., Schreiber, R.D., 1996. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 84, 431–442. Michel, T., Feron, O., 1997. Nitric oxide synthases: which, where, how, and why? Journal of Clinical Investigation 100, 2146–21552. Mishra, R., Chhatbar, C., Singh, S.K., 2012. HIV-1 Tat C-mediated regulation of tumor necrosis factor receptor-associated factor-3 by microRNA 32 in human microglia. Journal of Neuroinflammation 9, 131. Munir, M., Berg, M., 2013. The multiple faces of proteinkinase R in antiviral defense. Virulence 4, 85–89. Nakanishi, M., Goto, Y., Kitade, Y., 2005. 2-5A induces a conformational change in the ankyrin-repeat domain of RNase L. Proteins 60, 131–138. Nallagatla, S.R., Hwang, J., Toroney, R., Zheng, X., Cameron, C.E., Bevilacqua, P.C., 2007. 5 -triphosphate-dependent activation of PKR by RNAs with short stem-loops. Science 318, 1455–1458. Nanduri, S., Carpick, B.W., Yang, Y., Williams, B.R., Qin, J., 1998. Structure of the double-stranded RNA-binding domain of the protein kinase PKR reveals the molecular basis of its dsRNA-mediated activation. EMBO Journal 17, 5458–5465. Narasimhan, J., Potter, J.L., Haas, A.L., 1996. Conjugation of the 15-kDa interferoninduced ubiquitin homolog is distinct from that of ubiquitin. Journal of Biological Chemistry 271, 324–330. Nathans, R., Chu, C.Y., Serquina, A.K., Lu, C.C., Cao, H., Rana, T.M., 2009. Cellular microRNA and P bodies modulate host-HIV-1 interactions. Molecular Cell 34, 696–709. Newman, E.N., Holmes, R.K., Craig, H.M., Klein, K.C., Lingappa, J.R., Malim, M.H., Sheehy, A.M., 2005. Antiviral function of APOBEC3G can be dissociated from cytidine deaminase activity. Current Biology 15, 166–170. O’Connell, R.M., Taganov, K.D., Boldin, M.P., Cheng, G., Baltimore, D., 2007. MicroRNA-155 is induced during the macrophage inflammatory response. Proceedings of the National Academy of Sciences of the United States of America 104, 1604–1609. O’Donnell, K.A., Wentzel, E.A., Zeller, K.I., Dang, C.V., Mendell, J.T., 2005. c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435, 839–843. O’Shea, J.J., Holland, S.M., Staudt, L.M., 2013. JAKs and STATs in immunity, immunodeficiency, and cancer. New England Journal of Medicine 368, 161–170. Oh, H.M., Yu, C.R., Golestaneh, N., Amadi-Obi, A., Lee, Y.S., Eseonu, A., Mahdi, R.M., Egwuagu, C.E., 2011. STAT3 protein promotes T-cell survival and inhibits interleukin-2 production through up-regulation of Class O Forkhead transcription factors. Journal of Biological Chemistry 286, 30888–30897. Osiak, A., Utermöhlen, O., Niendorf, S., Horak, I., Knobeloch, K.P., 2005. ISG15, an interferon-stimulated ubiquitin-like protein, is not essential for STAT1 signaling and responses against vesicular stomatitis and lymphocytic choriomeningitis virus. Molecular Cell Biology 25, 6338–6345. Osterlund, P.I., Pietilä, T.E., Veckman, V., Kotenko, S.V., Julkunen, I., 2007. IFN regulatory factor family members differentially regulate the expression of type III IFN (IFN-␭) genes. Journal of Immunology 179, 3434–3442. Ostermann, E., Tuddenham, L., Macquin, C., Alsaleh, G., Schreiber-Becker, J., Tanguy, M., Bahram, S., Pfeffer, S., Georgel, P., 2012. Deregulation of type I IFN-dependent genes correlates with increased susceptibility to cytomegalovirus acute infection of dicer mutant mice. PLoS ONE 7, e43744. Papadopoulou, A.S., Dooley, J., Linterman, M.A., Pierson, W., Ucar, O., Kyewski, B., Zuklys, S., Hollander, G.A., Matthys, P., Gray, D.H., De Strooper, B., Liston, A., 2011. The thymic epithelial microRNA network elevates the threshold for infectionassociated thymic involution via miR-29a mediated suppression of the IFN-␣ receptor. Nature Immunology 13, 181–187. Park, H., Davies, M.V., Langland, J.O., Chang, H.W., Nam, Y.S., Tartaglia, J., Paoletti, E., Jacobs, B.L., Kaufman, R.J., Venkatesan, S., 1994. TAR RNA-binding protein is an inhibitor of the interferon-induced protein kinase PKR. Proceedings of the National Academy of Sciences of the United States of America 91, 4713–4717. Patterson, J.B., Samuel, C.E., 1995. Expression and regulation by interferon of a double-stranded-RNA-specific adenosine deaminase from human cells: evidence for two forms of the deaminase. Molecular Cell Biology 15, 5376–5388. Patterson, J.B., Thomis, D.C., Hans, S.L., Samuel, C.E., 1995. Mechanism of interferon action: double-stranded RNA-specific adenosine deaminase from human cells is inducible by alpha and gamma interferons. Virology 210, 508–511. Pedersen, I.M., Cheng, G., Wieland, S., Volinia, S., Croce, C.M., Chisari, F.V., David, M., 2007. Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature 449, 919–922.

Perske, C., Lahat, N., Sheffy Levin, S., Bitterman, H., Hemmerlein, B., Rahat, M.A., 2010. Loss of inducible nitric oxide synthase expression in the mouse renal cell carcinoma cell line RENCA is mediated by microRNA miR-146a. American Journal of Pathology 177, 2046–2054. Pindel, A., Sadler, A., 2011. The role of protein kinase R in the interferon response. Journal of Interferon & Cytokine Research 31, 59–70. Platanias, L.C., 2005. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nature Reviews Immunology 5, 375–386. Polioudakis, D., Bhinge, A.A., Killion, P.J., Lee, B.K., Abell, N.S., Iyer, V.R., 2013. A Myc-microRNA network promotes exit from quiescence by suppressing the interferon response and cell-cycle arrest genes. Nucleic Acids Research 41, 2239–2254. Ray, C.A., Black, R.A., Kronheim, S.R., Greenstreet, T.A., Sleath, P.R., Salvesen, G.S., Pickup, D.J., 1992. Viral inhibition of inflammation: cowpox virus encodes an inhibitor of the interleukin-1 beta converting enzyme. Cell 69, 597–604. Rebouillat, D., Marie, I., Hovanessian, A.G., 1998. Molecular cloning and characterization of two related and interferon-induced 56-kDa and 30-kDa proteins highly similar to 2’-5’ oligoadenylate synthetase. European Journal Biochem. 257, 319–330. Reeves, R.H., O’Hara, B.F., Pavan, W.J., Gearhart, J.D., Haller, O., 1988. Genetic mapping of the Mx influenza virus resistance gene within the region of mouse chromosome 16 that is homologous to human chromosome 21. Journal of Virology 62, 4372–4375. Reinsbach, S., Nazarov, P.V., Philippidou, D., Schmitt, M., Wienecke-Baldacchino, A., Muller, A., Vallar, L., Behrmann, I., Kreis, S., 2012. Dynamic regulation of microRNA expression following interferon-␥-induced gene transcription. RNA Biology 9, 978–989. Richmond, J.Y., Hamilton, L.D., 1969. Foot-and-mouth disease virus inhibition induced in mice by synthetic double-stranded RNA (polyriboinosinic and polyribocytidylic acids). Proceedings of the National Academy of Sciences of the United States of America 64, 81–86. Roberts, W.K., Hovanessian, A., Brown, R.E., Clemens, M.J., Kerr, I.M., 1976. Interferon-mediated protein kinase and low-molecular-weight inhibitor of protein synthesis. Nature 264, 477–480. Rodriguez, A., Griffiths-Jones, S., Ashurst, J.L., Bradley, A., 2004. Identification of mammalian microRNA host genes and transcription units. Genome Research 14, 1902–1910. Ruby, J.G., Jan, C.H., Bartel, D.P., 2007. Intronic microRNA precursors that bypass Drosha processing. Nature 448, 83–86. Rusch, L., Zhou, A., Silverman, R.H., 2000. Caspase-dependent apoptosis by 2 ,5 oligoadenylate activation of RNaseL is enhanced by IFN-␭. Journal of Interferon & Cytokine Research 20, 1091–1100. Sadler, A.J., Williams, B.R., 2008. Interferon-inducible antiviral effectors. Nature Reviews Immunology 8, 559–568. Saini, H.K., Griffiths-Jones, S., Enright, A.J., 2007. Genomic analysis of human microRNA transcripts. Proceedings of the National Academy of Sciences of the United States of America 104, 17719–17724. Samuel, C.E., 2011. Adenosine deaminases acting on RNA (ADARs) are both antiviral and proviral. Virology 411, 180–193. Sanghvi, V.R., Steel, L.F., 2011. The cellular TAR RNA binding protein, TRBP, promotes HIV-1 replication primarily by inhibiting the activation of double-stranded RNAdependent kinase PKR. Journal of Virology 85, 12614–12621. Sasai, M., Yamamoto, M., 2013. Pathogen recognition receptors: ligands and signaling pathways by toll-like receptors. International Reviews of Immunology 33, 116–133. Sato, M., Suemori, H., Hata, N., Asagiri, M., Ogasawara, K., Nakao, K., Nakaya, T., Katsuki, M., Noguchi, S., Tanaka, N., Taniguchi, T., 2000. Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-␣/␤ gene induction. Immunity 13, 539–548. Schmitt, M.J., Philippidou, D., Reinsbach, S.E., Margue, C., Wienecke-Baldacchino, A., Nashan, D., Behrmann, I., Kreis, S., 2012. Interferon-␥-induced activation of Signal Transducer and Activator of Transcription 1 (STAT1) up-regulates the tumor suppressing microRNA-29 family in melanoma cells. Cell Communication and Signaling 10, 41. Schoggins, J.W., Wilson, S.J., Panis, M., Murphy, M.Y., Jones, C.T., Bieniasz, P., Rice, C.M., 2011. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472, 481–485. Schumann, M., Gantke, T., Muhlberger, E., 2009. Ebola virus VP35 antagonizes PKR activity through its C-terminal interferon inhibitory domain. Virology Journal 83, 8993–8997. Sedger, L.M., Shows, D.M., Blanton, R.A., Peschon, J.J., Goodwin, R.G., Cosman, D., Wiley, S.R., 1999. IFN-gamma mediates a novel antiviral activity through dynamic modulation of TRAIL and TRAIL receptor expression. Journal of Immunology 163, 920–926. Sheppard, P., Kindsvogel, W., Xu, W., Henderson, K., Schlutsmeyer, S., Whitmore, T.E., Kuestner, R., Garrigues, U., Birks, C., Roraback, J., Ostrander, C., Dong, D., Shin, J., Presnell, S., Fox, B., Haldeman, B., Cooper, E., Taft, D., Gilbert, T., Grant, F.J., Tackett, M., Krivan, W., McKnight, G., Clegg, C., Foster, D., Klucher, K.M., 2003. IL-28. IL-29 and their class II cytokine receptor IL-28R. Nature Immunology 4, 63–68. Silva, L.F., Jones, C., 2012. Two microRNAs encoded within the bovine herpesvirus 1 latency-related gene promote cell survival by interacting with RIG-I and stimulating NF-␬B-dependent transcription and beta interferon signaling pathways. Journal of Virology 86, 1670–1682. Silva, V.A., Polesskaya, A., Sousa, T.A., Corrêa, V.M., André, N.D., Reis, R.I., Kettelhut, I.C., Harel-Bellan, A., De Lucca, F.L., 2011. Expression and cellular localization

L.M. Sedger / Molecular Immunology 56 (2013) 781–793 of microRNA-29b and RAX, an activator of the RNA-dependent protein kinase (PKR), in the retina of streptozotocin-induced diabetic rats. Molecular Vision 17, 2228–2240. Skaug, B., Chen, Z.J., 2010. Emerging role of ISG15 in antiviral immunity. Cell 143, 187–190. Smith, A.J., Li, Q., Wietgrefe, S.W., Schacker, T.W., Reilly, C.S., Haase, A.T., 2010. Host genes associated with HIV-1 replication in lymphatic tissue. Journal of Immunology 185, 5417–5424. Smith, H.C., Bennett, R.P., Kizilyer, A., McDougall, W.M., Prohaska, K.M., 2012. Functions and regulation of the APOBEC family of proteins. Seminars in Cell & Developmental Biology 23, 258–268. Staeheli, P., Grob, R., Meier, E., Sutcliffe, J.G., Haller, O., 1988. Influenza virussusceptible mice carry Mx genes with a large deletion or a nonsense mutation. Molecular Cell Biology 8, 4518–4523. Stewart, C.K., Li, J., Golovan, S.P., 2008. Adverse effects induced by short hairpin RNA expression in porcine fetal fibroblasts. Biochemical and Biophysical Research Communications 370, 113–117. Stojdl, D.F., Abraham, N., Knowles, S., Marius, R., Brasey, A., Lichty, B.D., Brown, E.G., Sonenberg, N., Bell, J.C., 2000. The murine double-stranded RNA-dependent protein kinase PKR is required for resistance to vesicular stomatitis virus. Journal of Virology 74, 9580–9585. Su, C., Hou, Z., Zhang, C., Tian, Z., Zhang, J., 2011. Ectopic expression of microRNA-155 enhances innate antiviral immunity against HBV infection in human hepatoma cells. Virology Journal 8, 354. Suppiah, V., Moldovan, M., Ahlenstiel, G., Berg, T., Weltman, M., Abate, M.L., Bassendine, M., Spengler, U., Dore, G.J., Powell, E., Riordan, S., Sheridan, D., Smedile, A., Fragomeli, V., Müller, T., Bahlo, M., Stewart, G.J., Booth, D.R., George, J., 2009. IL28B is associated with response to chronic hepatitis C interferon-␣ and ribavirin therapy. Nature Genetics 41, 1100–1104. Szenthe, K., Koroknai, A., Banati, F., Bathori, Z., Lozsa, R., Burgyan, J., Wolf, H., Salamon, D., Nagy, K., Niller, H.H., Minarovits, J., 2013. The 5 regulatory sequences of active miR-146a promoters are hypomethylated and associated with euchromatic histone modification marks in B lymphoid cells. Biochemical and Biophysical Research Communications 433, 489–495. Tanaka, N., Kawakami, T., Taniguchi, T., 1993. Recognition DNA sequences of interferon regulatory factor 1 (IRF-1) and IRF-2, regulators of cell growth and the interferon system. Molecular Cell Biology 13, 4531–4538. Tanaka, Y., Marusawa, H., Seno, H., Matsumoto, Y., Ueda, Y., Kodama, Y., Endo, Y., Yamauchi, J., Matsumoto, T., Takaori-Kondo, A., Ikai, I., Chiba, T., 2006. Anti-viral protein APOBEC3G is induced by interferon-␣ stimulation in human hepatocytes. Biochemical and Biophysical Research Communications 341, 314–319. Tarassishin, L., Loudig, O., Bauman, A., Shafit-Zagardo, B., Suh, H.S., Lee, S.C., 2011. Interferon regulatory factor 3 inhibits astrocyte inflammatory gene expression through suppression of the proinflammatory miR-155 and miR-155*. Glia 59, 1911–1922. Tran, N., Hutvagner, G., 2013. Biogenesis and the regulation of the maturation of miRNAs. Essays in Biochemistry 54, 17–28. Turan, K., Mibayashi, M., Sugiyama, K., Saito, S., Numajiri, A., Nagata, K., 2004. Nuclear MxA proteins form a complex with influenza virus NP and inhibit the transcription of the engineered influenza virus genome. Nucleic Acids Research 32, 643–652. Uzé, G., Monneron, D., 2007. IL-28 and IL-29: newcomers to the interferon family. Biochimie 89, 729–734. Valencia-Sanchez, M.A., Liu, J., Hannon, G.J., Parker, R., 2006. Control of translation and mRNA degradation by miRNAs and siRNAs. Genes & Development 20, 515–524. Wahl, S.M., Greenwell-Wild, T., Vázquez, N., 2007. HIV accomplices and adversaries in macrophage infection. Journal of Leukocyte Biology 80, 973–983. Wang, F.X., Huang, J., Zhang, H., Ma, X., Zhang, H., 2008. APOBEC3G upregulation by alpha interferon restricts human immunodeficiency virus type 1 infection in human peripheral plasmacytoid dendritic cells. Journal of General Virology 89, 722–730. Weber, F., Haller, O., Kochs, G., 2000. MxA GTPase blocks reporter gene expression of reconstituted Thogoto virus ribonucleoprotein complexes. Journal of Virology 74, 560–563. Wei, L., Vahedi, G., Sun, H.W., Watford, W.T., Takatori, H., Ramos, H.L., Takahashi, H., Liang, J., Gutierrez-Cruz, G., Zang, C., Peng, W., O’Shea, J.J., Kanno, Y., 2010. Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation. Immunity 32, 840–851. Wiesen, J.L., Tomasi, T.B., 2009. Dicer is regulated by cellular stresses and interferons. Molecular Immunology 46, 1222–1228. Wong, S.K., Lazinski, D.W., 2002. Replicating hepatitis delta virus RNA is edited in the nucleus by the small form of ADAR1. Proceedings of the National Academy of Sciences of the United States of America 99, 15118–15123. Wreschner, D.H., McCauley, J.W., Skehel, J.J., Kerr, I.M., 1981. Interferon actionsequence specificity of the ppp(A2 p)nA-dependent ribonuclease. Nature 289, 414–417. Wulczyn, F.G., Smirnova, L., Rybak, A., Brandt, C., Kwidzinski, E., Ninnemann, O., Strehle, M., Seiler, A., Schumacher, S., Nitsch, R., 2007. Post-transcriptional regulation of the let-7 microRNA during neural cell specification. FASEB Journal 21, 415–426.

793

Xi, Y., Day, S.L., Jackson, R.J., Ranasinghe, C., 2012. Role of novel type I interferon epsilon in viral infection and mucosal immunity. Mucosal Immunology 5, 610–622. Xiang, Y., Wang, Z., Murakami, J., Plummer, S., Klein, E.A., Carpten, J.D., Trent, J.M., Isaacs, W.B., Casey, G., Silverman, R.H., 2003. Effects of RNaseL mutations associated with prostate cancer on apoptosis induced by 2 ,5 -oligoadenylates. Cancer Research 63, 6795–6801. Xie, X., Lu, J., Kulbokas, E.J., Golub, T.R., Mootha, V., Lindblad-Toh, K., Lander, E.S., Kellis, M., 2007. Systematic discovery of regulatory motifs in human promoters and 3 UTRs by comparison of several mammals. Nature 434, 338–345. Xu, C., Ren, G., Cao, G., Chen, Q., Shou, P., Zheng, C., Du, L., Han, X., Jiang, M., Yang, Q., Lin, L., Wang, G., Yu, P., Zhang, X., Cao, W., Brewer, G., Wang, Y., Shi, Y., 2013. MiR-155 regulates immune modulatory properties of mesenchymal stem cells by targeting TAK1-binding protein 2. Journal of Biological Chemistry 288, 11074–11079. Yadav, D., Ngolab, J., Lim, R.S., Krishnamurthy, S., Bui, J.D., 2009. Cutting edge: downregulation of MHC class I-related chain A on tumor cells by IFN-␥-induced microRNA. Journal of Immunology 182, 39–43. Yao, R., Ma, Y.L., Liang, W., Li, H.H., Ma, Z.J., Yu, X., Liao, Y.H., 2012. MicroRNA-155 modulates Treg and Th17 cells differentiation and Th17 cell function by targeting SOCS1. PLoS ONE 7, e46082. Yi, R., Qin, Y., Macara, I.G., Cullen, B.R., 2003. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes & Development 17, 3011–3016. Ying, S.Y., Lin, S.L., 2005. Intronic microRNAs. Biochemical and Biophysical Research Communications 326, 515–520. Yuan, W., Krug, R.M., 2001. Influenza B virus NS1 protein inhibits conjugation of the interferon-induced ubiquitin-like ISG15 protein. EMBO Journal 20, 362–371. Yuan, Y., Kasar, S., Underbayev, C., Vollenweider, D., Salerno, E., Kotenko, S.V., Raveche, E., 2012. Role of microRNA-15a in autoantibody production in interferon-augmented murine model of lupus. Molecular Immunology 52, 61–70. Zawislak, C.L., Beaulieu, A.M., Loeb, G.B., Karo, J., Canner, D., Bezman, N.A., Lanier, L.L., Rudensky, A.Y., Sun, J.C., 2013. Stage-specific regulation of natural killer cell homeostasis and response against viral infection by microRNA-155. Proceedings of the National Academy of Sciences of the United States of America 110, 6967–6972. Zeng, Y., Yi, R., Cullen, B.R., 2003. MicroRNAs and small interfering RNAs can inhibit mRNA expression by similar mechanisms. Proceedings of the National Academy of Sciences of the United States of America 100, 9779–9784. Zhang, H., Kolb, F.A., Brondani, V., Billy, E., Filipowicz, W., 2002. Human Dicer preferentially cleaves dsRNAs at their termini without a requirement for ATP. EMBO Journal 21, 5875–5885. Zhao, C., Denison, C., Huibregtse, J.M., Gygi, S., Krug, R.M., 2005. Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Proceedings of the National Academy of Sciences of the United States of America 102, 10200–10205. Zhou, A., Hassel, B.A., Silverman, R.H., 1993. Expression cloning of 2-5Adependent RNAase: a uniquely regulated mediator of interferon action. Cell 72, 753–765. Zhou, A., Paranjape, J., Brown, T.L., Nie, H., Naik, S., Dong, B., Chang, A., Trapp, B., Fairchild, R., Colmenares, C., Silverman, R.H., 1997. Interferon action and apoptosis are defective in mice devoid of 2 ,5 -oligoadenylate-dependent RNaseL. EMBO Journal 16, 6355–6363. Zhou, C., Yu, Q., Chen, L., Wang, J., Zheng, S., Zhang, J., 2012a. A miR-1231 binding site polymorphism in the 3 UTR of IFNAR1 is associated with hepatocellular carcinoma susceptibility. Gene 507, 95–98. Zhou, H., Huang, X., Cui, H., Luo, X., Tang, Y., Chen, S., Wu, L., Shen, N., 2010. miR-155 and its star-form partner miR-155* cooperatively regulate type I interferon production by human plasmacytoid dendritic cells. Blood 116, 5885–5894. Zhou, L., Wang, X., Wang, Y.J., Zhou, Y., Hu, S., Ye, L., Hou, W., Li, H., Ho, W.Z., 2009. Activation of toll-like receptor-3 induces interferon-lambda expression in human neuronal cells. Neuroscience 159, 629–637. Zhou, R., Gong, A.Y., Eischeid, A.N., Chen, X.M., 2012b. miR-27b targets KSRP to coordinate TLR4-mediated epithelial defense against Cryptosporidium parvum infection. PLoS Pathogens 8, e1002702. Zhou, Z., Hamming, O.J., Ank, N., Paludan, S.R., Nielsen, A.L., Hartmann, R., 2007. Type III interferon (IFN) induces a type I IFN-like response in a restricted subset of cells through signaling pathways involving both the Jak-STAT pathway and the mitogen-activated protein kinases. Journal of Virology 81, 7749–7758. Zhu, H., Butera, M., Nelson, D.R., Liu, C., 2005. Novel type I interferon IL-28A suppresses hepatitis C viral RNA replication. Virology Journal 2, 80. Zhu, Y., Cherukuri, N.C., Jackel, J.N., Wu, Z., Crary, M., Buckley, K.J., Bisaro, D.M., Parris, D.S., 2012. Characterization of the RNA silencing suppression activity of the Ebola virus VP35 protein in plants and mammalian cells. Journal of Virology 86, 3038–3049. Zimmermann, P., Mänz, B., Haller, O., Schwemmle, M., Kochs, G., 2011. The viral nucleoprotein determines Mx sensitivity of influenza A viruses. Journal of Virology 85, 8133–8140.