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Diverse roles of HDAC6 in viral infection: Implications for antiviral therapy
JPT-06896; No of Pages 6 Pharmacology & Therapeutics xxx (2016) xxx–xxx
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Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera
Diverse roles of HDAC6 in viral infection: Implications for antiviral therapy Linlin Zhang a, Angela Ogden b, Ritu Aneja b, Jun Zhou a,c,⁎ a
State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China Department of Biology, Georgia State University, Atlanta, GA 30303, USA Institute of Biomedical Sciences, College of Life Sciences, Key Laboratory of Animal Resistance of Shandong Province, Key Laboratory of Molecular and Nano Probes of the Ministry of Education, Shandong Normal University, Jinan 250014, China
b c
a r t i c l e
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a b s t r a c t Histone deacetylase 6 (HDAC6), a cytoplasmic enzyme important for many biological processes, has recently emerged as a critical regulator of viral infection. HDAC6 exerts this function either directly, via orchestrating various stages of the viral life cycle, or indirectly via modulating cytokine production by host cells. The broad influence of HDAC6 on viral pathogenesis suggests that this protein may represent an antiviral target. However, the feasibility of targeting HDAC6 and the optimal strategy by which this could be accomplished cannot simply be concluded from individual studies. The primary challenge in developing HDAC6-targeted therapies is to understand how its antiviral effect can be selectively harnessed. As a springboard for future investigations, in this review we recapitulate recent findings on the diverse roles of HDAC6 in viral infection and discuss its alluring potential as a novel antiviral target. © 2016 Elsevier Inc. All rights reserved.
Keywords: HDAC6 Viral infection Viral pathogenesis Antiviral therapy
Contents 1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. From the perspective of the host: effect of HDAC6 on host IFN response . . . . . . . . 3. From the perspective of the invader: multifarious effects of HDAC6 on the viral life cycle 4. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Histone deacetylase 6 (HDAC6) is a member of the HDAC family that contains two functional catalytic domains and a ubiquitin-binding
Abbreviations: CBP, cAMP response element-binding protein (CREB) binding protein; HCV, hepatitis C virus; HDAC6, histone deacetylase 6; HIV, human immunodeficiency virus; IAV, influenza A virus; IFN, interferon; IRF3, IFN regulatory factor 3; KSHV, Kaposi's sarcoma-associated herpesvirus; NF-κB, nuclear factor κB; PKCα, protein kinase C alpha; RIG-I, retinoic-acid-inducible gene-I; SeV, Sendai virus; Tat, transactivator of transcription; Vif, viral infectivity factor. ⁎ Corresponding author at: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China. Tel.: + 86 22 2350 4946; fax: +86 22 2350 4946. E-mail address: [email protected] (J. Zhou).
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domain. Unlike most other HDACs, HDAC6 is predominantly localized in the cytoplasm and deacetylates non-histone proteins, such as αtubulin, Hsp90, and cortactin (Hubbert et al., 2002; Kovacs et al., 2005; Zhang et al., 2007). By its deacetylase and ubiquitin-binding activities and interaction with partner proteins, HDAC6 plays an important role in a variety of biological processes, including cell migration, cell– cell interaction, autophagy, and ciliary homeostasis. Recent evidence suggests that HDAC6 is also an important regulator of viral infection, through both deacetylase-dependent and -independent mechanisms. A more detailed understanding of the intricate involvement of HDAC6 in the viral life cycle might reveal unique opportunities for antiviral therapy. Towards this end, in this review we summarize recent studies about the integral role played by HDAC6 during viral infection and its varied mechanisms of action. We begin from the perspective of the
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Please cite this article as: Zhang, L., et al., Diverse roles of HDAC6 in viral infection: Implications for antiviral therapy, Pharmacology & Therapeutics (2016), http://dx.doi.org/10.1016/j.pharmthera.2016.04.005
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host and discuss the impact of HDAC6 on the interferon (IFN) response, and then we shift perspective to that of the virus itself and delineate the wide-ranging effects of HDAC6 on various stages of the viral life cycle. 2. From the perspective of the host: effect of HDAC6 on host IFN response Central to combating viral infections are type I IFNs (Perry et al., 2005; Haller et al., 2006; Stetson & Medzhitov, 2006), especially IFN-β, which is produced by many cell types as a key component of the innate immune response to viral infection (Nagarajan, 2011; Sin et al., 2012). Expression of the gene encoding IFN-β is modulated by the transcription factors IFN regulatory factor 3 (IRF3) and nuclear factor κB (NFκB) (Hiscott, 2007; Severa & Fitzgerald, 2007). Early studies suggest that phosphorylation and nuclear translocation of IRF3 are the only regulated steps of IRF3 transcriptional activity (Yoneyama et al., 2002; Panne et al., 2007); however, subsequent research reveals that acetylation is also involved (Nusinzon & Horvath, 2006), suggesting a possible role for HDACs in modulating IFN-β levels. When cells are infected with Sendai virus (SeV) or treated with double-stranded RNA (dsRNA), the expression of IFN-β is induced by the binding of IRF3 and NF-κB to its promoter. Interestingly, Nusinzon and Horvath demonstrate that HDAC inhibitors suppress the production of IFN-β by decreasing the transcriptional activity of IRF3 but not NF-κB (Nusinzon & Horvath, 2006). By RNA interference, the authors further show that it is HDAC6 that functions as a coactivator for IFN-β induction. HDAC6-silenced cells exhibit diminished IFN-β production and accordingly increased viral replication (Nusinzon & Horvath, 2006). Though this study does
not pinpoint the exact mechanism through which HDAC6 regulates IFN-β expression, it provides the first evidence that HDAC6 is a key regulator of innate response against viral infection. Further mechanistic studies by Zhu et al. suggest a relationship between protein kinase C alpha (PKCα), HDAC6, and β-catenin in the regulation of IRF3 transcriptional activity and IFN-β production (Zhu et al., 2011) (Fig. 1). Following SeV infection, PKCα is activated by autophosphorylation, permitting it to recruit and phosphorylate HDAC6. Thereafter, activated HDAC6 causes deacetylation and nuclear translocation of β-catenin. Finally, β-catenin functions as a coactivator for IRF3mediated transcription in the nucleus (Yang et al., 2010; Zhu et al., 2011) (Fig. 1). It is worthwhile to note that this study, for the first time, reveals the upstream and downstream components and signaling pathways involved in HDAC6-modulated IFN-β production. Subsequently, Chattopadhyay et al. reveal that HDAC6-mediated deacetylation of β-catenin is a prerequisite for the interaction between IRF3 and its coactivator cAMP response element-binding protein (CREB) binding protein (CBP), which is bridged by β-catenin (Chattopadhyay et al., 2013) (Fig. 1). The authors also show that HDAC6-knockout mice are more susceptible to SeV infection (Chattopadhyay et al., 2013). Intriguingly, a recent study by Choi et al. further demonstrates that HDAC6 regulates RNA virus infection at the very beginning, the sensing step, in a deacetylasedependent manner (Choi et al., 2016). HDAC6 transiently interacts with the viral sensor, retinoic-acid-inducible gene-I (RIG-I), and specially deacetylates lysine 909 of RIG-I in response to RNA viral infection, which is essential to RIG-I viral RNA-sensing activity and the activation of downstream signaling pathway (Choi et al., 2016). HDAC6-knockout mice are sensitive to lethal RNA viral infection and show decreased
Fig. 1. HDAC6 inhibits SeV infection by upregulating IFN-β expression. SeV infection causes the self-phosphorylation and activation of PKCα. Activated PKCα then recruits and phosphorylates HDAC6. Phosphorylated HDAC6 in turn deacetylates β-catenin and induces its translocation to the nucleus, where it functions as a coactivator for IRF3-mediated transcription. CBP, another coactivator, is phosphorylated by PKCβ. The interaction between IRF3 and CBP is bridged by β-catenin. The formed stable initiation complex induces IFN-β transcription.
Please cite this article as: Zhang, L., et al., Diverse roles of HDAC6 in viral infection: Implications for antiviral therapy, Pharmacology & Therapeutics (2016), http://dx.doi.org/10.1016/j.pharmthera.2016.04.005
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production of IFN-β and interleukin-6 (IL-6) (Choi et al., 2016). In addition, Wang et al. confirm the antiviral effect of HDAC6 using embryonic stem cells overexpressing HDAC6 and HDAC6-transgenic mice (Wang et al., 2015). Collectively, these studies elegantly demonstrate that HDAC6 can upregulate the host IFN-β response to thwart viral pathogenesis and insinuate that potentiation of HDAC6 responses might protect against viral infection. 3. From the perspective of the invader: multifarious effects of HDAC6 on the viral life cycle Few steps in the viral life cycle are untouched by HDAC6, although the precise effects vary depending on the specific virus and cellular context. The viral life cycle, for the sake of simplicity, is artificially divided into several successive steps, including entry, intracellular transport, uncoating, replication, assembly, and release (Damm & Pelkmans, 2006; Marsh & Helenius, 2006). In addition, evasion of host immune responses is necessary for viral survival. Viruses hijack host molecular machinery to progress through their life cycle and to circumvent elimination by the immune system. Intuitively, an ideal antiviral target would be one that is involved in many life cycle steps and prevents immune evasion so that viral inhibition is robust. In this light, HDAC6 seems to constitute an appealing antiviral target because it affects viral entry, intracellular transport, uncoating, replication, immune escape, reactivation, and infectivity, which we describe in the following section. 3.1. Entry Different viruses adopt disparate strategies to enter host cells. For animal viruses, there are typically two strategies for entry. Enveloped viruses usually enter host cells via membrane fusion, whereas nonenveloped viruses mainly enter via endocytosis, such as clathrin- and caveolae/lipid raft-mediated endocytosis (Smith & Helenius, 2004; Mercer et al., 2010; Thorley et al., 2010; Yamauchi & Helenius, 2013). Both the two entry processes rely on host cell membrane dynamics, which is controlled by the cytoskeleton (Jaqaman & Grinstein, 2012). Because HDAC6 is a key regulator of microtubules and microfilaments, the notion arises that it could potentially regulate viral entry. This hypothesis is supported by studies of human immunodeficiency virus (HIV), an enveloped virus that enters host cells mainly via membrane fusion. Valenzuela-Fernandez et al. demonstrate that overexpression of HDAC6 reduces HIV infection and HIV envelope-triggered cell–cell fusion by inhibiting gp120-induced tubulin acetylation (ValenzuelaFernandez et al., 2005). Malinowsky et al. also report that overexpression of HDAC6 decreases virus–cell membrane fusion by reducing the level of acetylated tubulin (Malinowsky et al., 2008). Though the influence of HDAC6 on post-entry events could also contribute to its inhibitory effects on HIV infection, the evidence is still compelling that HDAC6 blocks HIV entry by changing membrane dynamics and thus inhibiting virus–cell fusion and syncytium formation. 3.2. Intracellular transport Viruses that have entered host cells cannot move effectively towards specific destinations by diffusion alone (Sodeik, 2000). They are faced with the problem of trafficking through the viscous cytoplasm towards the nucleus or other location for replication and then back to the cell membrane for release. Many viruses take advantage of the microtubule-based transport machinery of host cells for active transport within the cell (Ploubidou & Way, 2001; Leopold & Pfister, 2006; Dodding & Way, 2011; Ward, 2011). Some viruses induce significant acetylation of microtubules, which affects polarized cargo transport (Reed et al., 2006; Hammond et al., 2010). Influenza A virus (IAV) has been reported to be one of the viruses that can enhance microtubule acetylation to facilitate its intracellular trafficking (Husain &
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Harrod, 2011). HDAC6 inhibits IAV infection by negatively regulating IAV transport within the host cell via deacetylation of microtubules (Husain & Cheung, 2014) (Fig. 2). Other viruses, such as Kaposi's sarcoma-associated herpesvirus (KSHV) and HIV-1, have also been shown to increase microtubule acetylation (Naranatt et al., 2005; Valenzuela-Fernandez et al., 2005; Sabo et al., 2013). HDAC6 may negatively regulate the infection of these viruses as well by interrupting their transport along microtubules. 3.3. Uncoating Before the genome of a virus can be replicated in a host cell, uncoating must take place, which is a complex, multistep process involving various regulators. HDAC6 has been shown to be required for efficient uncoating and infection of IAV via its ubiquitin-binding domain in a deacetylase-independent manner (Banerjee et al., 2014) (Fig. 2). Banerjee et al. show that IAV infection is reduced in HDAC6-depleted human epithelial cells and HDAC6-knockout mouse embryonic fibroblasts (MEFs). By stepwise analysis, the authors reveal that HDAC6 is required in post-fusion events, namely uncoating and nuclear import. IAV hijacks the aggresome pathway of the host cell by mimicking misfolded protein aggregates tagged with unanchored polyubiquitin chains and activating an HDAC6-dependent pathway (I. Banerjee et al., 2014). HDAC6 binds capsid-associated ubiquitin chains and motor proteins to transfer opposing physical forces to break apart the capsid and release viral ribonucleoproteins into the cytoplasm (Banerjee et al., 2014) (Fig. 2). Collectively, these findings point to a role of HDAC6 in promoting IAV infection by assisting in viral uncoating, an important aspect when considering the potential of potentiating HDAC6 responses as an antiviral strategy. 3.4. Replication HDAC6 is involved in the replication of certain viruses, in some instances playing an inhibitory role and in others an activating one. In the case of HIV-1, HDAC6 suppresses replication by binding to the transactivator of transcription (Tat) protein, which is necessary for HIV-1 replication (Huo et al., 2011). HDAC6 interacts with Tat in the cytoplasm and deacetylates Tat at K28, which suppress Tat-mediated transactivation of the HIV-1 promoter. Tat is thus prevented from forming a ribonucleoprotein complex with cyclin T1 and the transactivation-responsive RNA (Huo et al., 2011). Lucera et al. confirm the inhibitory effects of HDAC6 on HIV-1 replication by using HDAC inhibitors (Lucera et al., 2014). Both the pan-HDAC inhibitor vorinostat and the HDAC6-specific inhibitor tubacin could enhance the kinetics and efficiency of HIV-1 reverse transcription, nuclear import, and integration (Lucera et al., 2014). Thus, these findings strongly suggest that HDAC6 is a cellular inhibitor of HIV-1 replication and infection. Recently, HDAC6 has been shown to inhibit the replication of genetically engineered oncolytic herpes simplex virus (oHSV) in glioma cells by shuttling post-entry oHSV towards lysosomes to prevent the release of the viral genome into the nucleus (Nakashima et al., 2015). On the other hand, HDAC6 promotes hepatitis C virus (HCV) replication. Kozlov et al. reveal that HDAC6-specific inhibitor tubastatin A suppresses the proliferation of the HCV replicon in cultured human hepatocytes (Kozlov et al., 2014). Moreover, they show that pyridine hydroxamic acids, potent and highly specific anti-HCV agents, suppress HCV replication by inhibiting HDAC6 and inducing hyperacetylation of microtubules (Kozlov et al., 2015). HDAC6 may also be involved in IAV replication. Husain and Harrod demonstrate that IAV infection causes HDAC6 cleavage by caspase-3 (Husain & Harrod, 2009), resulting in removal of most of its ubiquitin-binding domain, which may influence its activity to process misfolded proteins and to regulate Hsp90. The latter function has been demonstrated to be involved in IAV replication (Naito et al., 2007), so HDAC6 may impact IAV replication, although this topic needs further study. Altogether, these reports highlight the fact that
Please cite this article as: Zhang, L., et al., Diverse roles of HDAC6 in viral infection: Implications for antiviral therapy, Pharmacology & Therapeutics (2016), http://dx.doi.org/10.1016/j.pharmthera.2016.04.005
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Fig. 2. HDAC6 regulates IAV infection at different stages of the viral life cycle. IAV infection induces microtubule acetylation to facilitate viral transport in the host cell, and HDAC6 attenuates this process by deacetylating microtubules. IAV capsid fuses with the membrane of late endosomes and carries unanchored polyubiquitin chains, which are recognized by HDAC6. HDAC6 interacts with dynein, which transfers physical forces to break apart the viral capsid and release the viral genome into the cytoplasm.
HDAC6 can impact viral replication both positively and negatively, and effective HDAC6-targeting strategies may fundamentally differ between viral classes.
3.5. Immune escape and reactivation In addition to the regulation of certain stages of the viral life cycle, HDAC6 is involved in viral immune escape and reactivation. Lazaro et al. report that HDAC6 and Hsp90 form a chaperone complex to prevent the degradation of HIV-derived peptides (Lazaro et al., 2011). The stability of the peptides is essential for MHC-I-restricted epitope generation and subsequent recognition of the infected cells by virus-specific cytotoxic T cells (Lazaro et al., 2011). This study indicates a vital role for HDAC6 in epitope presentation to prevent HIV from achieving immune escape. However, HDAC6 has also been shown to be involved in the reactivation of latent HIV-1 and KSHV to a lytic phase of replication (Banerjee et al., 2012; Shin et al., 2014). Banerjee et al. show that the expression of HDAC6 is upregulated in JQ1-triggered reactivation of HIV-1, suggesting its positive role in viral reactivation (Banerjee et al., 2012). Shin et al. also demonstrate that inhibition of HDAC6 by tubacin could suppress valproic acid-stimulated reactivation of KSHV, while overexpression of HDAC6 is sufficient to reactivate KSHV from latency (Shin et al., 2014). Although it remains unclear whether viral reactivation is advantageous or disadvantageous, it is of great importance to unravel the triggers and suppressors of this process for future development and improvement of antiviral therapies.
3.6. Infectivity HDAC6 can minimize the infectivity of retroviruses like HIV-1. In the typical course of HIV-1 infection, the HIV-1 viral infectivity factor (Vif) binds to the antiviral cytidine deaminase apolipoprotein B mRNAediting enzyme, catalytic polypeptide-like 3G (APOBEC3G) and targets it for ubiquitination and degradation (Stopak et al., 2003; Shao et al., 2010). Valera et al. reveal that HDAC6 on the one hand interacts with Vif via its ubiquitin-binding domain and promotes the autophagic degradation of Vif, and on the other hand forms a complex with APOBEC3G and protects it from Vif-induced ubiquitination and proteasome degradation, thereby launching a two-pronged attack against HIV-1 infectivity (Valera et al., 2015). The authors further demonstrate that HDAC6 can reduce HIV-1 infectivity in a ubiquitin-binding domain- and deacetylase activity-dependent manner.
4. Concluding remarks A compelling body of evidence has established HDAC6 as a critical regulator of viral infection both through its actions on host antiviral response and on viral life cycle stages. Through deacetylase-dependent and -independent mechanisms, HDAC6 exerts complicated effects on the process of viral infection (as summarized in Table 1). From the perspective of the host, it is quite clear that HDAC6 acts as an antiviral factor by strengthening the host defense. From the perspective of the invaders, the regulatory roles of HDAC6 seem intricate due to the biological
Please cite this article as: Zhang, L., et al., Diverse roles of HDAC6 in viral infection: Implications for antiviral therapy, Pharmacology & Therapeutics (2016), http://dx.doi.org/10.1016/j.pharmthera.2016.04.005
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Table 1 An overview of the effects of HDAC6 on viral infection. Virus
Characterization Effects of HDAC6 (diameter in nm)
SeV
Enveloped, (−)ssRNA, 150–250
Inhibits SeV infection by upregulating IFN-β expression
HIV
Enveloped, (+)ssRNA, 90–120
Blocks HIV entry by inhibiting virus–cell membrane fusion and cell–cell fusion
Inhibits HIV replication by impairing Tat transactivation activity or impeding viral reverse transcription, nuclear import and integration
Prevents HIV from immune escape by acting as a chaperone and enhancing HIV peptide stability; Facilitates HIV reactivation since HDAC6 expression is upregulated during JQ1-induced reactivation Reduces HIV infectivity by targeting Vif for degradation IAV
Enveloped, (−)ssRNA, 50–120
Inhibits IAV intracellular transport by deacetylating microtubules
Facilitates IAV uncoating in a deacetylase-independent manner by transferring physical forces to break apart the capsid
HCV
Enveloped, (+)ssRNA, 45–60 KSHV Enveloped, dsDNA, 120–130
Promotes HCV replication
Facilitates KSHV reactivation
Methods used
References
RNA interference; inhibitors: TSA; HDAC6-knockout mice Overexpression; RNA interference; inhibitors: TSA, tubacin Overexpression; RNA interference; inhibitors: tubacin, vorinostat; HDAC6-knockout MEFs RNA interference; inhibitors: TSA N/A
(Nusinzon & Horvath, 2006; Zhu et al., 2011; Chattopadhyay et al., 2013)
Overexpression; RNA interference Overexpression; RNA interference; inhibitors: TSA, tubacin RNA interference; inhibitors: tubastatin A; HDAC6-knockout MEFs Inhibitors: tubastatin A, PHAs
(Valera et al., 2015)
Overexpression; inhibitors: TSA, tubacin
(Valenzuela-Fernandez et al., 2005; Malinowsky et al., 2008)
(Huo et al., 2011; Lucera et al., 2014)
(Lazaro et al., 2011) (Banerjee et al., 2012)
(Husain & Harrod, 2011; Husain & Cheung, 2014)
(Banerjee et al., 2014)
(Kozlov et al., 2014; Kozlov et al., 2015) (Shin et al., 2014)
Notes: SeV, Sendai virus; HIV, human immunodeficiency virus; IAV, Influenza A virus; HCV, hepatitis C virus; KSHV, Kaposi's sarcoma-associated herpesvirus; (−)ssRNA, negative-sense single-stranded RNA; (+)ssRNA, positive-sense single-stranded RNA; dsDNA, double-stranded DNA; TSA, trichostatin A; PHAs, pyridine hydroxamic acids; MEFs, mouse embryonic fibroblasts; N/A, not applicable.
diversity of the invaders and the host. In general, the inhibitory effects of HDAC6 on viral life cycle are largely attributed to its deacetylase activity, whereas the ubiquitin-binding ability of its ZnF-UBP domain is sometimes deleterious. For example, HDAC6 inhibits the intracellular transport of IAV through the deacetylation of microtubules but promotes the uncoating of IAV via its ZnF-UBP domain. In this case, specific disturbance of the ubiquitin-binding ability of HDAC6 but leaving its deacetylase activity unhampered might be a promising strategy to treat IAV infection. In the case of HIV infection, both the deacetylase and the ubiquitin-binding activities are beneficial to the host. Thus, bolstering HDAC6-mediated processes could be a very robust treatment for HIV infection. Theoretically, when HDAC6 exhibits inhibitory effects on viral infection, HDAC6 stimulators that are able to enhance its expression or activity may be employed to potentiate the antiviral effects of endogenous
HDAC6 to restrict viral infection. On the contrary, when HDAC6 facilitates infection, HDAC6-specific inhibitors would serve as promising reagents for fighting viral infection. Currently, most of the conclusions are drawn from in vitro studies at the cellular level. Only a few studies evaluate the effects of HDAC6 on viral infection at the animal level (as summarized in Table 2), all of which use HDAC6 deficient or transgenic mice instead of HDAC6-targeting drugs. Although the effects of HDAC6 are clear in each study, the results could be quite different when HDAC6targeting drugs are applied to animals. Interdisciplinary studies combining chemical synthesis with animal studies might be a promising direction for future research. Overall, however, it is doubtless that HDAC6 functions as a vital regulator of the infection process for various types of viruses, which represents a solid basis for investigating it further as an antiviral target. Any attempt to block the infection of a certain type of virus by targeting
Table 2 A summary of animal experiments in studying the potential roles of HDAC6 in viral infection. Animal studies
Roles of HDAC6
References
Wild-type and HDAC6-knockout mice were intranasally infected with SeV Wild-type and HDAC6-knockout mice were intravenously infected with VSV-Indiana. Wild-type and HDAC6 transgenic mice were infected with avian H5N1 influenza virus.
HDAC6 inhibits SeV infection by promoting the formation of IRF3/β-catenin/ CBP transcription initiation complex. HDAC6 inhibits VSV-Indiana infection through deacetylation of RIG-I and subsequent activation of RIG-I-mediated anti-viral sensing pathway. HDAC6 transgenic mice show enhanced resistance to avian H5N1 influenza virus infection.
(Chattopadhyay et al., 2013) (Choi et al., 2016) (Wang et al., 2015)
Notes: SeV, Sendai virus; VSV-Indiana, vesicular stomatitis virus—Indiana strain.
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HDAC6 should take its complicated regulatory effects into account to avoid or reduce serious adverse effects on the host. In all likelihood, effective therapeutic strategies based on HDAC6 will need to be tailored to specific viral infections, which might be possible given that the promoting or inhibitory effects of HDAC6 are often mediated through distinct domains of HDAC6 with different binding partners. Conflict of interest statement The authors declare that there are no conflicts of interest. Acknowledgments This work was supported by grants from the National Natural Science Foundation of China (31471262) and the National Science and Technology Major Project of China (2012ZX10001-006). References Banerjee, C., Archin, N., Michaels, D., Belkina, A. C., Denis, G. V., Bradner, J., ... Montano, M. (2012). BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol 92, 1147–1154. Banerjee, I., Miyake, Y., Nobs, S. P., Schneider, C., Horvath, P., Kopf, M., ... Yamauchi, Y. (2014). Influenza a virus uses the aggresome processing machinery for host cell entry. Science 346, 473–477. Chattopadhyay, S., Fensterl, V., Zhang, Y., Veleeparambil, M., Wetzel, J. L., & Sen, G. C. (2013). Inhibition of viral pathogenesis and promotion of the septic shock response to bacterial infection by IRF-3 are regulated by the acetylation and phosphorylation of its coactivators. MBio 4. Choi, S. J., Lee, H. C., Kim, J. H., Park, S. Y., Kim, T. H., Lee, W. K., ... Lee, J. S. (2016). HDAC6 regulates cellular viral RNA sensing by deacetylation of RIG-I. EMBO J 35, 429–442. Damm, E. M., & Pelkmans, L. (2006). Systems biology of virus entry in mammalian cells. Cell Microbiol 8, 1219–1227. Dodding, M. P., & Way, M. (2011). Coupling viruses to dynein and kinesin-1. EMBO J 30, 3527–3539. Haller, O., Kochs, G., & Weber, F. (2006). The interferon response circuit: Induction and suppression by pathogenic viruses. Virology 344, 119–130. Hammond, J. W., Huang, C. F., Kaech, S., Jacobson, C., Banker, G., & Verhey, K. J. (2010). Posttranslational modifications of tubulin and the polarized transport of kinesin-1 in neurons. Mol Biol Cell 21, 572–583. Hiscott, J. (2007). Convergence of the NF-kappaB and IRF pathways in the regulation of the innate antiviral response. Cytokine Growth Factor Rev 18, 483–490. Hubbert, C., Guardiola, A., Shao, R., Kawaguchi, Y., Ito, A., Nixon, A., ... Yao, T. P. (2002). HDAC6 is a microtubule-associated deacetylase. Nature 417, 455–458. Huo, L., Li, D., Sun, X., Shi, X., Karna, P., Yang, W., ... Zhou, J. (2011). Regulation of tat acetylation and transactivation activity by the microtubule-associated deacetylase HDAC6. J Biol Chem 286, 9280–9286. Husain, M., & Cheung, C. Y. (2014). Histone deacetylase 6 inhibits influenza a virus release by downregulating the trafficking of viral components to the plasma membrane via its substrate, acetylated microtubules. J Virol 88, 11229–11239. Husain, M., & Harrod, K. S. (2009). Influenza a virus-induced caspase-3 cleaves the histone deacetylase 6 in infected epithelial cells. FEBS Lett 583, 2517–2520. Husain, M., & Harrod, K. S. (2011). Enhanced acetylation of alpha-tubulin in influenza a virus infected epithelial cells. FEBS Lett 585, 128–132. Jaqaman, K., & Grinstein, S. (2012). Regulation from within: The cytoskeleton in transmembrane signaling. Trends Cell Biol 22, 515–526. Kovacs, J. J., Murphy, P. J., Gaillard, S., Zhao, X., Wu, J. T., Nicchitta, C. V., ... Yao, T. P. (2005). HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol Cell 18, 601–607. Kozlov, M. V., Kleymenova, A. A., Konduktorov, K. A., Malikova, A. Z., & Kochetkov, S. N. (2014). Selective inhibitor of histone deacetylase 6 (tubastatin a) suppresses proliferation of hepatitis C virus replicon in culture of human hepatocytes. Biochemistry (Mosc) 79, 637–642. Kozlov, M. V., Kleymenova, A. A., Romanova, L. I., Konduktorov, K. A., Kamarova, K. A., Smirnova, O. A., ... Kochetkov, S. N. (2015). Pyridine hydroxamic acids are specific anti-HCV agents affecting HDAC6. Bioorg Med Chem Lett 25, 2382–2385. Lazaro, E., Kadie, C., Stamegna, P., Zhang, S. C., Gourdain, P., Lai, N. Y., ... Le Gall, S. (2011). Variable HIV peptide stability in human cytosol is critical to epitope presentation and immune escape. J Clin Invest 121, 2480–2492. Leopold, P. L., & Pfister, K. K. (2006). Viral strategies for intracellular trafficking: Motors and microtubules. Traffic 7, 516–523. Lucera, M. B., Tilton, C. A., Mao, H., Dobrowolski, C., Tabler, C. O., Haqqani, A. A., ... Tilton, J. C. (2014). The histone deacetylase inhibitor vorinostat (SAHA) increases the
susceptibility of uninfected CD4+ T cells to HIV by increasing the kinetics and efficiency of postentry viral events. J Virol 88, 10803–10812. Malinowsky, K., Luksza, J., & Dittmar, M. T. (2008). Susceptibility to virus–cell fusion at the plasma membrane is reduced through expression of HIV gp41 cytoplasmic domains. Virology 376, 69–78. Marsh, M., & Helenius, A. (2006). Virus entry: Open sesame. Cell 124, 729–740. Mercer, J., Schelhaas, M., & Helenius, A. (2010). Virus entry by endocytosis. Annu Rev Biochem 79, 803–833. Nagarajan, U. (2011). Induction and function of IFNbeta during viral and bacterial infection. Crit Rev Immunol 31, 459–474. Naito, T., Momose, F., Kawaguchi, A., & Nagata, K. (2007). Involvement of Hsp90 in assembly and nuclear import of influenza virus RNA polymerase subunits. J Virol 81, 1339–1349. Nakashima, H., Kaufmann, J. K., Wang, P. Y., Nguyen, T., Speranza, M. C., Kasai, K., ... Chiocca, E. A. (2015). 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Curr Opin Cell Biol 13, 97–105. Reed, N. A., Cai, D., Blasius, T. L., Jih, G. T., Meyhofer, E., Gaertig, J., & Verhey, K. J. (2006). Microtubule acetylation promotes kinesin-1 binding and transport. Curr Biol 16, 2166–2172. Sabo, Y., Walsh, D., Barry, D. S., Tinaztepe, S., de Los Santos, K., Goff, S. P., ... Naghavi, M. H. (2013). HIV-1 induces the formation of stable microtubules to enhance early infection. Cell Host Microbe 14, 535–546. Severa, M., & Fitzgerald, K. A. (2007). TLR-mediated activation of type I IFN during antiviral immune responses: Fighting the battle to win the war. Curr Top Microbiol Immunol 316, 167–192. Shao, Q. J., Wang, Y. D., Hildreth, J. E. K., & Liu, B. D. (2010). Polyubiquitination of APOBEC3G is essential for its degradation by HIV-1 Vif. J Virol 84, 4840–4844. Shin, H. J., DeCotiis, J., Giron, M., Palmeri, D., & Lukac, D. M. (2014). Histone deacetylase classes I and II regulate Kaposi's sarcoma-associated herpesvirus reactivation. J Virol 88, 1281–1292. 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Contents lists available at ScienceDirect
Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera
Diverse roles of HDAC6 in viral infection: Implications for antiviral therapy Linlin Zhang a, Angela Ogden b, Ritu Aneja b, Jun Zhou a,c,⁎ a
State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China Department of Biology, Georgia State University, Atlanta, GA 30303, USA Institute of Biomedical Sciences, College of Life Sciences, Key Laboratory of Animal Resistance of Shandong Province, Key Laboratory of Molecular and Nano Probes of the Ministry of Education, Shandong Normal University, Jinan 250014, China
b c
a r t i c l e
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a b s t r a c t Histone deacetylase 6 (HDAC6), a cytoplasmic enzyme important for many biological processes, has recently emerged as a critical regulator of viral infection. HDAC6 exerts this function either directly, via orchestrating various stages of the viral life cycle, or indirectly via modulating cytokine production by host cells. The broad influence of HDAC6 on viral pathogenesis suggests that this protein may represent an antiviral target. However, the feasibility of targeting HDAC6 and the optimal strategy by which this could be accomplished cannot simply be concluded from individual studies. The primary challenge in developing HDAC6-targeted therapies is to understand how its antiviral effect can be selectively harnessed. As a springboard for future investigations, in this review we recapitulate recent findings on the diverse roles of HDAC6 in viral infection and discuss its alluring potential as a novel antiviral target. © 2016 Elsevier Inc. All rights reserved.
Keywords: HDAC6 Viral infection Viral pathogenesis Antiviral therapy
Contents 1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. From the perspective of the host: effect of HDAC6 on host IFN response . . . . . . . . 3. From the perspective of the invader: multifarious effects of HDAC6 on the viral life cycle 4. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Histone deacetylase 6 (HDAC6) is a member of the HDAC family that contains two functional catalytic domains and a ubiquitin-binding
Abbreviations: CBP, cAMP response element-binding protein (CREB) binding protein; HCV, hepatitis C virus; HDAC6, histone deacetylase 6; HIV, human immunodeficiency virus; IAV, influenza A virus; IFN, interferon; IRF3, IFN regulatory factor 3; KSHV, Kaposi's sarcoma-associated herpesvirus; NF-κB, nuclear factor κB; PKCα, protein kinase C alpha; RIG-I, retinoic-acid-inducible gene-I; SeV, Sendai virus; Tat, transactivator of transcription; Vif, viral infectivity factor. ⁎ Corresponding author at: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China. Tel.: + 86 22 2350 4946; fax: +86 22 2350 4946. E-mail address: [email protected] (J. Zhou).
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domain. Unlike most other HDACs, HDAC6 is predominantly localized in the cytoplasm and deacetylates non-histone proteins, such as αtubulin, Hsp90, and cortactin (Hubbert et al., 2002; Kovacs et al., 2005; Zhang et al., 2007). By its deacetylase and ubiquitin-binding activities and interaction with partner proteins, HDAC6 plays an important role in a variety of biological processes, including cell migration, cell– cell interaction, autophagy, and ciliary homeostasis. Recent evidence suggests that HDAC6 is also an important regulator of viral infection, through both deacetylase-dependent and -independent mechanisms. A more detailed understanding of the intricate involvement of HDAC6 in the viral life cycle might reveal unique opportunities for antiviral therapy. Towards this end, in this review we summarize recent studies about the integral role played by HDAC6 during viral infection and its varied mechanisms of action. We begin from the perspective of the
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host and discuss the impact of HDAC6 on the interferon (IFN) response, and then we shift perspective to that of the virus itself and delineate the wide-ranging effects of HDAC6 on various stages of the viral life cycle. 2. From the perspective of the host: effect of HDAC6 on host IFN response Central to combating viral infections are type I IFNs (Perry et al., 2005; Haller et al., 2006; Stetson & Medzhitov, 2006), especially IFN-β, which is produced by many cell types as a key component of the innate immune response to viral infection (Nagarajan, 2011; Sin et al., 2012). Expression of the gene encoding IFN-β is modulated by the transcription factors IFN regulatory factor 3 (IRF3) and nuclear factor κB (NFκB) (Hiscott, 2007; Severa & Fitzgerald, 2007). Early studies suggest that phosphorylation and nuclear translocation of IRF3 are the only regulated steps of IRF3 transcriptional activity (Yoneyama et al., 2002; Panne et al., 2007); however, subsequent research reveals that acetylation is also involved (Nusinzon & Horvath, 2006), suggesting a possible role for HDACs in modulating IFN-β levels. When cells are infected with Sendai virus (SeV) or treated with double-stranded RNA (dsRNA), the expression of IFN-β is induced by the binding of IRF3 and NF-κB to its promoter. Interestingly, Nusinzon and Horvath demonstrate that HDAC inhibitors suppress the production of IFN-β by decreasing the transcriptional activity of IRF3 but not NF-κB (Nusinzon & Horvath, 2006). By RNA interference, the authors further show that it is HDAC6 that functions as a coactivator for IFN-β induction. HDAC6-silenced cells exhibit diminished IFN-β production and accordingly increased viral replication (Nusinzon & Horvath, 2006). Though this study does
not pinpoint the exact mechanism through which HDAC6 regulates IFN-β expression, it provides the first evidence that HDAC6 is a key regulator of innate response against viral infection. Further mechanistic studies by Zhu et al. suggest a relationship between protein kinase C alpha (PKCα), HDAC6, and β-catenin in the regulation of IRF3 transcriptional activity and IFN-β production (Zhu et al., 2011) (Fig. 1). Following SeV infection, PKCα is activated by autophosphorylation, permitting it to recruit and phosphorylate HDAC6. Thereafter, activated HDAC6 causes deacetylation and nuclear translocation of β-catenin. Finally, β-catenin functions as a coactivator for IRF3mediated transcription in the nucleus (Yang et al., 2010; Zhu et al., 2011) (Fig. 1). It is worthwhile to note that this study, for the first time, reveals the upstream and downstream components and signaling pathways involved in HDAC6-modulated IFN-β production. Subsequently, Chattopadhyay et al. reveal that HDAC6-mediated deacetylation of β-catenin is a prerequisite for the interaction between IRF3 and its coactivator cAMP response element-binding protein (CREB) binding protein (CBP), which is bridged by β-catenin (Chattopadhyay et al., 2013) (Fig. 1). The authors also show that HDAC6-knockout mice are more susceptible to SeV infection (Chattopadhyay et al., 2013). Intriguingly, a recent study by Choi et al. further demonstrates that HDAC6 regulates RNA virus infection at the very beginning, the sensing step, in a deacetylasedependent manner (Choi et al., 2016). HDAC6 transiently interacts with the viral sensor, retinoic-acid-inducible gene-I (RIG-I), and specially deacetylates lysine 909 of RIG-I in response to RNA viral infection, which is essential to RIG-I viral RNA-sensing activity and the activation of downstream signaling pathway (Choi et al., 2016). HDAC6-knockout mice are sensitive to lethal RNA viral infection and show decreased
Fig. 1. HDAC6 inhibits SeV infection by upregulating IFN-β expression. SeV infection causes the self-phosphorylation and activation of PKCα. Activated PKCα then recruits and phosphorylates HDAC6. Phosphorylated HDAC6 in turn deacetylates β-catenin and induces its translocation to the nucleus, where it functions as a coactivator for IRF3-mediated transcription. CBP, another coactivator, is phosphorylated by PKCβ. The interaction between IRF3 and CBP is bridged by β-catenin. The formed stable initiation complex induces IFN-β transcription.
Please cite this article as: Zhang, L., et al., Diverse roles of HDAC6 in viral infection: Implications for antiviral therapy, Pharmacology & Therapeutics (2016), http://dx.doi.org/10.1016/j.pharmthera.2016.04.005
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production of IFN-β and interleukin-6 (IL-6) (Choi et al., 2016). In addition, Wang et al. confirm the antiviral effect of HDAC6 using embryonic stem cells overexpressing HDAC6 and HDAC6-transgenic mice (Wang et al., 2015). Collectively, these studies elegantly demonstrate that HDAC6 can upregulate the host IFN-β response to thwart viral pathogenesis and insinuate that potentiation of HDAC6 responses might protect against viral infection. 3. From the perspective of the invader: multifarious effects of HDAC6 on the viral life cycle Few steps in the viral life cycle are untouched by HDAC6, although the precise effects vary depending on the specific virus and cellular context. The viral life cycle, for the sake of simplicity, is artificially divided into several successive steps, including entry, intracellular transport, uncoating, replication, assembly, and release (Damm & Pelkmans, 2006; Marsh & Helenius, 2006). In addition, evasion of host immune responses is necessary for viral survival. Viruses hijack host molecular machinery to progress through their life cycle and to circumvent elimination by the immune system. Intuitively, an ideal antiviral target would be one that is involved in many life cycle steps and prevents immune evasion so that viral inhibition is robust. In this light, HDAC6 seems to constitute an appealing antiviral target because it affects viral entry, intracellular transport, uncoating, replication, immune escape, reactivation, and infectivity, which we describe in the following section. 3.1. Entry Different viruses adopt disparate strategies to enter host cells. For animal viruses, there are typically two strategies for entry. Enveloped viruses usually enter host cells via membrane fusion, whereas nonenveloped viruses mainly enter via endocytosis, such as clathrin- and caveolae/lipid raft-mediated endocytosis (Smith & Helenius, 2004; Mercer et al., 2010; Thorley et al., 2010; Yamauchi & Helenius, 2013). Both the two entry processes rely on host cell membrane dynamics, which is controlled by the cytoskeleton (Jaqaman & Grinstein, 2012). Because HDAC6 is a key regulator of microtubules and microfilaments, the notion arises that it could potentially regulate viral entry. This hypothesis is supported by studies of human immunodeficiency virus (HIV), an enveloped virus that enters host cells mainly via membrane fusion. Valenzuela-Fernandez et al. demonstrate that overexpression of HDAC6 reduces HIV infection and HIV envelope-triggered cell–cell fusion by inhibiting gp120-induced tubulin acetylation (ValenzuelaFernandez et al., 2005). Malinowsky et al. also report that overexpression of HDAC6 decreases virus–cell membrane fusion by reducing the level of acetylated tubulin (Malinowsky et al., 2008). Though the influence of HDAC6 on post-entry events could also contribute to its inhibitory effects on HIV infection, the evidence is still compelling that HDAC6 blocks HIV entry by changing membrane dynamics and thus inhibiting virus–cell fusion and syncytium formation. 3.2. Intracellular transport Viruses that have entered host cells cannot move effectively towards specific destinations by diffusion alone (Sodeik, 2000). They are faced with the problem of trafficking through the viscous cytoplasm towards the nucleus or other location for replication and then back to the cell membrane for release. Many viruses take advantage of the microtubule-based transport machinery of host cells for active transport within the cell (Ploubidou & Way, 2001; Leopold & Pfister, 2006; Dodding & Way, 2011; Ward, 2011). Some viruses induce significant acetylation of microtubules, which affects polarized cargo transport (Reed et al., 2006; Hammond et al., 2010). Influenza A virus (IAV) has been reported to be one of the viruses that can enhance microtubule acetylation to facilitate its intracellular trafficking (Husain &
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Harrod, 2011). HDAC6 inhibits IAV infection by negatively regulating IAV transport within the host cell via deacetylation of microtubules (Husain & Cheung, 2014) (Fig. 2). Other viruses, such as Kaposi's sarcoma-associated herpesvirus (KSHV) and HIV-1, have also been shown to increase microtubule acetylation (Naranatt et al., 2005; Valenzuela-Fernandez et al., 2005; Sabo et al., 2013). HDAC6 may negatively regulate the infection of these viruses as well by interrupting their transport along microtubules. 3.3. Uncoating Before the genome of a virus can be replicated in a host cell, uncoating must take place, which is a complex, multistep process involving various regulators. HDAC6 has been shown to be required for efficient uncoating and infection of IAV via its ubiquitin-binding domain in a deacetylase-independent manner (Banerjee et al., 2014) (Fig. 2). Banerjee et al. show that IAV infection is reduced in HDAC6-depleted human epithelial cells and HDAC6-knockout mouse embryonic fibroblasts (MEFs). By stepwise analysis, the authors reveal that HDAC6 is required in post-fusion events, namely uncoating and nuclear import. IAV hijacks the aggresome pathway of the host cell by mimicking misfolded protein aggregates tagged with unanchored polyubiquitin chains and activating an HDAC6-dependent pathway (I. Banerjee et al., 2014). HDAC6 binds capsid-associated ubiquitin chains and motor proteins to transfer opposing physical forces to break apart the capsid and release viral ribonucleoproteins into the cytoplasm (Banerjee et al., 2014) (Fig. 2). Collectively, these findings point to a role of HDAC6 in promoting IAV infection by assisting in viral uncoating, an important aspect when considering the potential of potentiating HDAC6 responses as an antiviral strategy. 3.4. Replication HDAC6 is involved in the replication of certain viruses, in some instances playing an inhibitory role and in others an activating one. In the case of HIV-1, HDAC6 suppresses replication by binding to the transactivator of transcription (Tat) protein, which is necessary for HIV-1 replication (Huo et al., 2011). HDAC6 interacts with Tat in the cytoplasm and deacetylates Tat at K28, which suppress Tat-mediated transactivation of the HIV-1 promoter. Tat is thus prevented from forming a ribonucleoprotein complex with cyclin T1 and the transactivation-responsive RNA (Huo et al., 2011). Lucera et al. confirm the inhibitory effects of HDAC6 on HIV-1 replication by using HDAC inhibitors (Lucera et al., 2014). Both the pan-HDAC inhibitor vorinostat and the HDAC6-specific inhibitor tubacin could enhance the kinetics and efficiency of HIV-1 reverse transcription, nuclear import, and integration (Lucera et al., 2014). Thus, these findings strongly suggest that HDAC6 is a cellular inhibitor of HIV-1 replication and infection. Recently, HDAC6 has been shown to inhibit the replication of genetically engineered oncolytic herpes simplex virus (oHSV) in glioma cells by shuttling post-entry oHSV towards lysosomes to prevent the release of the viral genome into the nucleus (Nakashima et al., 2015). On the other hand, HDAC6 promotes hepatitis C virus (HCV) replication. Kozlov et al. reveal that HDAC6-specific inhibitor tubastatin A suppresses the proliferation of the HCV replicon in cultured human hepatocytes (Kozlov et al., 2014). Moreover, they show that pyridine hydroxamic acids, potent and highly specific anti-HCV agents, suppress HCV replication by inhibiting HDAC6 and inducing hyperacetylation of microtubules (Kozlov et al., 2015). HDAC6 may also be involved in IAV replication. Husain and Harrod demonstrate that IAV infection causes HDAC6 cleavage by caspase-3 (Husain & Harrod, 2009), resulting in removal of most of its ubiquitin-binding domain, which may influence its activity to process misfolded proteins and to regulate Hsp90. The latter function has been demonstrated to be involved in IAV replication (Naito et al., 2007), so HDAC6 may impact IAV replication, although this topic needs further study. Altogether, these reports highlight the fact that
Please cite this article as: Zhang, L., et al., Diverse roles of HDAC6 in viral infection: Implications for antiviral therapy, Pharmacology & Therapeutics (2016), http://dx.doi.org/10.1016/j.pharmthera.2016.04.005
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Fig. 2. HDAC6 regulates IAV infection at different stages of the viral life cycle. IAV infection induces microtubule acetylation to facilitate viral transport in the host cell, and HDAC6 attenuates this process by deacetylating microtubules. IAV capsid fuses with the membrane of late endosomes and carries unanchored polyubiquitin chains, which are recognized by HDAC6. HDAC6 interacts with dynein, which transfers physical forces to break apart the viral capsid and release the viral genome into the cytoplasm.
HDAC6 can impact viral replication both positively and negatively, and effective HDAC6-targeting strategies may fundamentally differ between viral classes.
3.5. Immune escape and reactivation In addition to the regulation of certain stages of the viral life cycle, HDAC6 is involved in viral immune escape and reactivation. Lazaro et al. report that HDAC6 and Hsp90 form a chaperone complex to prevent the degradation of HIV-derived peptides (Lazaro et al., 2011). The stability of the peptides is essential for MHC-I-restricted epitope generation and subsequent recognition of the infected cells by virus-specific cytotoxic T cells (Lazaro et al., 2011). This study indicates a vital role for HDAC6 in epitope presentation to prevent HIV from achieving immune escape. However, HDAC6 has also been shown to be involved in the reactivation of latent HIV-1 and KSHV to a lytic phase of replication (Banerjee et al., 2012; Shin et al., 2014). Banerjee et al. show that the expression of HDAC6 is upregulated in JQ1-triggered reactivation of HIV-1, suggesting its positive role in viral reactivation (Banerjee et al., 2012). Shin et al. also demonstrate that inhibition of HDAC6 by tubacin could suppress valproic acid-stimulated reactivation of KSHV, while overexpression of HDAC6 is sufficient to reactivate KSHV from latency (Shin et al., 2014). Although it remains unclear whether viral reactivation is advantageous or disadvantageous, it is of great importance to unravel the triggers and suppressors of this process for future development and improvement of antiviral therapies.
3.6. Infectivity HDAC6 can minimize the infectivity of retroviruses like HIV-1. In the typical course of HIV-1 infection, the HIV-1 viral infectivity factor (Vif) binds to the antiviral cytidine deaminase apolipoprotein B mRNAediting enzyme, catalytic polypeptide-like 3G (APOBEC3G) and targets it for ubiquitination and degradation (Stopak et al., 2003; Shao et al., 2010). Valera et al. reveal that HDAC6 on the one hand interacts with Vif via its ubiquitin-binding domain and promotes the autophagic degradation of Vif, and on the other hand forms a complex with APOBEC3G and protects it from Vif-induced ubiquitination and proteasome degradation, thereby launching a two-pronged attack against HIV-1 infectivity (Valera et al., 2015). The authors further demonstrate that HDAC6 can reduce HIV-1 infectivity in a ubiquitin-binding domain- and deacetylase activity-dependent manner.
4. Concluding remarks A compelling body of evidence has established HDAC6 as a critical regulator of viral infection both through its actions on host antiviral response and on viral life cycle stages. Through deacetylase-dependent and -independent mechanisms, HDAC6 exerts complicated effects on the process of viral infection (as summarized in Table 1). From the perspective of the host, it is quite clear that HDAC6 acts as an antiviral factor by strengthening the host defense. From the perspective of the invaders, the regulatory roles of HDAC6 seem intricate due to the biological
Please cite this article as: Zhang, L., et al., Diverse roles of HDAC6 in viral infection: Implications for antiviral therapy, Pharmacology & Therapeutics (2016), http://dx.doi.org/10.1016/j.pharmthera.2016.04.005
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Table 1 An overview of the effects of HDAC6 on viral infection. Virus
Characterization Effects of HDAC6 (diameter in nm)
SeV
Enveloped, (−)ssRNA, 150–250
Inhibits SeV infection by upregulating IFN-β expression
HIV
Enveloped, (+)ssRNA, 90–120
Blocks HIV entry by inhibiting virus–cell membrane fusion and cell–cell fusion
Inhibits HIV replication by impairing Tat transactivation activity or impeding viral reverse transcription, nuclear import and integration
Prevents HIV from immune escape by acting as a chaperone and enhancing HIV peptide stability; Facilitates HIV reactivation since HDAC6 expression is upregulated during JQ1-induced reactivation Reduces HIV infectivity by targeting Vif for degradation IAV
Enveloped, (−)ssRNA, 50–120
Inhibits IAV intracellular transport by deacetylating microtubules
Facilitates IAV uncoating in a deacetylase-independent manner by transferring physical forces to break apart the capsid
HCV
Enveloped, (+)ssRNA, 45–60 KSHV Enveloped, dsDNA, 120–130
Promotes HCV replication
Facilitates KSHV reactivation
Methods used
References
RNA interference; inhibitors: TSA; HDAC6-knockout mice Overexpression; RNA interference; inhibitors: TSA, tubacin Overexpression; RNA interference; inhibitors: tubacin, vorinostat; HDAC6-knockout MEFs RNA interference; inhibitors: TSA N/A
(Nusinzon & Horvath, 2006; Zhu et al., 2011; Chattopadhyay et al., 2013)
Overexpression; RNA interference Overexpression; RNA interference; inhibitors: TSA, tubacin RNA interference; inhibitors: tubastatin A; HDAC6-knockout MEFs Inhibitors: tubastatin A, PHAs
(Valera et al., 2015)
Overexpression; inhibitors: TSA, tubacin
(Valenzuela-Fernandez et al., 2005; Malinowsky et al., 2008)
(Huo et al., 2011; Lucera et al., 2014)
(Lazaro et al., 2011) (Banerjee et al., 2012)
(Husain & Harrod, 2011; Husain & Cheung, 2014)
(Banerjee et al., 2014)
(Kozlov et al., 2014; Kozlov et al., 2015) (Shin et al., 2014)
Notes: SeV, Sendai virus; HIV, human immunodeficiency virus; IAV, Influenza A virus; HCV, hepatitis C virus; KSHV, Kaposi's sarcoma-associated herpesvirus; (−)ssRNA, negative-sense single-stranded RNA; (+)ssRNA, positive-sense single-stranded RNA; dsDNA, double-stranded DNA; TSA, trichostatin A; PHAs, pyridine hydroxamic acids; MEFs, mouse embryonic fibroblasts; N/A, not applicable.
diversity of the invaders and the host. In general, the inhibitory effects of HDAC6 on viral life cycle are largely attributed to its deacetylase activity, whereas the ubiquitin-binding ability of its ZnF-UBP domain is sometimes deleterious. For example, HDAC6 inhibits the intracellular transport of IAV through the deacetylation of microtubules but promotes the uncoating of IAV via its ZnF-UBP domain. In this case, specific disturbance of the ubiquitin-binding ability of HDAC6 but leaving its deacetylase activity unhampered might be a promising strategy to treat IAV infection. In the case of HIV infection, both the deacetylase and the ubiquitin-binding activities are beneficial to the host. Thus, bolstering HDAC6-mediated processes could be a very robust treatment for HIV infection. Theoretically, when HDAC6 exhibits inhibitory effects on viral infection, HDAC6 stimulators that are able to enhance its expression or activity may be employed to potentiate the antiviral effects of endogenous
HDAC6 to restrict viral infection. On the contrary, when HDAC6 facilitates infection, HDAC6-specific inhibitors would serve as promising reagents for fighting viral infection. Currently, most of the conclusions are drawn from in vitro studies at the cellular level. Only a few studies evaluate the effects of HDAC6 on viral infection at the animal level (as summarized in Table 2), all of which use HDAC6 deficient or transgenic mice instead of HDAC6-targeting drugs. Although the effects of HDAC6 are clear in each study, the results could be quite different when HDAC6targeting drugs are applied to animals. Interdisciplinary studies combining chemical synthesis with animal studies might be a promising direction for future research. Overall, however, it is doubtless that HDAC6 functions as a vital regulator of the infection process for various types of viruses, which represents a solid basis for investigating it further as an antiviral target. Any attempt to block the infection of a certain type of virus by targeting
Table 2 A summary of animal experiments in studying the potential roles of HDAC6 in viral infection. Animal studies
Roles of HDAC6
References
Wild-type and HDAC6-knockout mice were intranasally infected with SeV Wild-type and HDAC6-knockout mice were intravenously infected with VSV-Indiana. Wild-type and HDAC6 transgenic mice were infected with avian H5N1 influenza virus.
HDAC6 inhibits SeV infection by promoting the formation of IRF3/β-catenin/ CBP transcription initiation complex. HDAC6 inhibits VSV-Indiana infection through deacetylation of RIG-I and subsequent activation of RIG-I-mediated anti-viral sensing pathway. HDAC6 transgenic mice show enhanced resistance to avian H5N1 influenza virus infection.
(Chattopadhyay et al., 2013) (Choi et al., 2016) (Wang et al., 2015)
Notes: SeV, Sendai virus; VSV-Indiana, vesicular stomatitis virus—Indiana strain.
Please cite this article as: Zhang, L., et al., Diverse roles of HDAC6 in viral infection: Implications for antiviral therapy, Pharmacology & Therapeutics (2016), http://dx.doi.org/10.1016/j.pharmthera.2016.04.005
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