Cytosolic DNA recognition for triggering innate immune responses

Available online at www.sciencedirect.com

Advanced Drug Delivery Reviews 60 (2008) 847 – 857 www.elsevier.com/locate/addr

Cytosolic DNA recognition for triggering innate immune responses☆ Akinori Takaoka a,⁎, Tadatsudu Taniguchi b,⁎ a

Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan Department of Immunology, Graduate School of Medicine & Faculty of Medicine, University of Tokyo, Tokyo, Japan

b

Received 6 December 2007; accepted 18 December 2007 Available online 31 December 2007

Abstract The detection of microbial components by pattern recognition receptors (PRRs) and the subsequent triggering of innate immune responses constitute the first line of defense against infections. Recently, much attention has been focused on cytosolic nucleic acid receptors; the activation of these receptors commonly evokes a robust innate immune response, the hallmark of which is the induction of type I interferon (IFN) genes. In addition to receptors for RNA, receptors that detect DNA exposed in the cytosol and activate innate immune responses have long been thought to exist. Recently, DAI (DLM-1/ZBP1) has been identified as a candidate cytosolic DNA sensor. Cytosolic signaling by DNA-activated DAI (DLM1/ZBP1) signaling results in activation of the two pathways of gene transcription critical to innate immune responses, the IRF and NF-κB pathways. In this review, we summarize our current view of activation mechanism and immunological roles of DAI (DLM-1/ZBP1) and related molecules. In addition, we also discuss the issue of self vs. non-self DNA recognition by DAI (DLM-1/ZBP1) and other DNA sensors in terms of the possible involvement in autoimmune abnormalities. © 2007 Elsevier B.V. All rights reserved. Keywords: Innate immunity; DNA; Pattern recognition receptor; DAI (DLM-1/ZBP1); Interferon-regulatory factor

Contents 1. 2. 3. 4.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Background of cytosolic DNA recognition pathways . . . . . . . . . . . . . . Identification of new DNA-sensing molecule, DAI (DLM-1/ZBP1) . . . . . . . Signaling pathways downstream of DAI (DLM-1/ZBP1) . . . . . . . . . . . . 4.1. IRF pathway. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. NF-κB pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . What is the molecular basis of DAI (DLM-1/ZBP1) activation by DNA? . . . . Redundancy in the cytosolic DNA-sensing system . . . . . . . . . . . . . . . Family related to DAI (DLM-1/ZBP1) . . . . . . . . . . . . . . . . . . . . . . 7.1. ADARs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. PKZ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3. E3L . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biological roles of cytosolic DNA recognition pathway in microbial infection . Self or non-self recognition through cytosolic DNA recognition pathway and its autoimmune abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and future prospects . . . . . . . . . . . . . . . . . . . . . . . .

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This review is part of the Advanced Drug Delivery Reviews theme issue on “Toll-like Receptor and Pattern Sensing for Evoking Immune Response”. ⁎ Corresponding authors. Takaoka is to be contacted at Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan. Tel.: +81 11 706 5020; fax: +81 11 706 7541. Taniguchi, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan. Tel.: +81 3 5841 3375; fax: +81 3 5841 3450. E-mail addresses: [email protected] (A. Takaoka), [email protected] (T. Taniguchi). 0169-409X/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2007.12.002

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1. Introduction The discrimination of self and non-self molecules is fundamental to immunity. It has long been perceived that this process critically involves the acquisition of immunological tolerance in the body. In the adaptive immune system, tolerance is mainly achieved by deleting or suppressing the lymphocytes reacting with self-molecules in the periphery. In the innate immune system, it has been thought that pathogen recognition receptors evolved to selectively recognize molecular patterns associated with pathogens, termed pathogen-associated molecular patterns (PAMPs), such that they usually do not recognize self-molecules. Recently, an additional view of how the innate immune system does not react to self-molecules has gained attention: Self-molecules are potentially immunoreactive but are sequestered in cells such that they are not “sensed” by the immune system. In this context, the most extensively studied topic to date is how nucleic acids, namely DNA/RNA, that are “design drawing for lives” essential for all living organisms [1], also function as activators of the immune system. It has long been known that double-stranded RNAs, which are not usually found in mammalian cells, and DNA evoke immune responses. Indeed, induction of type I interferon genes, one of the hallmarks of innate immune response as described below, by mammalian DNAs has been reported more than four decades ago [2,3]. As representative cytokines in immune responses, interferon (IFN) family members [4–6] are currently divided into three types, type I IFNs (see below), type II IFN (IFN-γ) and type III IFNs (IFN-λs), on the basis of their structural and functional properties (Table 1). The type I IFNs [7] consist of Table 1 The interferon family members Type Subtype

Receptor

Gene locus a

Expression pattern

I

IFN-α IFN-β IFN-ɛ IFN-ω IFN-κ

IFNAR-1/IFNAR-2 IFNAR-1/IFNAR-2 IFNAR-1/IFNAR-2 IFNAR-1/IFNAR-2 IFNAR-1/IFNAR-2

9p21 9p21 9p21 9p21 9p21

IFN-ζ b

IFNAR-1/IFNAR-2

None

II

IFN-γ

IFNGR-1/IFNGR2

12q24.1

III

IFN-λ1 (IL-29) IFN-λ2 (IL-28A) IFN-λ3 (IL-28B)

IL-28Rα/IL-10R2

19q1

Ubiquitously expressed Ubiquitously expressed Uterus, ovary Leukocytes Selectively expressed in epidermal keratinocytes Spleen, thymus, lymph node Activated T cell, macrophage, NK cell Ubiquitously expressed

IL-28Rα/IL-10R2

19q1

Ubiquitously expressed

IL-28Rα/IL-10R2

19q1

Ubiquitously expressed

a b

Human. Found in mice only.

IFN-αs, -β, -ω, -ɛ [8,9], and -κ [10], and others. Type I IFNs are a family of structurally related cytokines with a hallmark function of anti-viral activity, and of note are its roles in innate immunity [11–14]. Most of the intensive studies have focused mainly on IFN-α/β. These members are commonly induced in cells infected by various RNA and DNA viruses to confer an anti-viral state on uninfected cells. It has been the great interest in the last three decades how the type I IFN gene is induced by viruses. Indeed, molecular analyses of the type I IFN gene induction have been one of the prototypes of how mammalian genes are switched on and off in cells [15–18]. It was in this context that a family of transcription factors, IFN-regulatory factors (IRFs), were discovered and extensively studied [19– 23]. The second question is then raised — What is the molecular switch that mounts an anti-viral defense system, i.e., the innate immune system, characterized by the massive production of type I IFNs and other immune mediators? In this regard, it has recently been established that the activation of this process is triggered by the detection of highly conserved, microbe-specific pattern structures (also known as PAMPs) through pattern recognition receptors (PRRs) [24]. More recently, the discovery of PRRs has opened a new avenue for IRF-IFN research, expanding their roles beyond anti-viral innate immune responses. Indeed, the IRFfamily, consisting of nine members, has been extensively studied in the gene induction programmes activated by TLRs and other pathogen recognition receptors [25–28]. Among many PRRs identified thus far, TLRs [29–31] belong to a transmembrane type that recognize PAMPs in either the extracellular space or intracellular compartments such as endosomes and lysosomes. Recently, cytosolic recognition systems for innate immunity have been gradually elucidated. Both DNA and RNA derived from not only microbes but also host cells show an immunostimulatory activity when transfected into the cytosol [2,32–35]. However, cellular receptors for nucleic acids have remained unknown until the recent identification of the retinoic acid-inducible gene I (RIGI) family members as cytosolic RNA sensors [36]. More recently, a candidate cytosolic DNA sensor called DAI (DNA-dependent activator of IRFs, previously known as DLM-1 or ZBP1) has also been reported [37]. In this review, we focus on the cytosolic DNA recognition pathway(s) and its biological roles in viral and bacterial infections. Furthermore, we discuss self or non-self DNA discrimination through this pathway and its possible effect on autoimmune abnormalities. 2. Background of cytosolic DNA recognition pathways How do host cells sense the invasion of pathogens? It is now established that the detection of microbial components by PRRs is the first line of defense in triggering innate immune responses. Recent rapid progress in studies on pathogen recognition has

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facilitated the identification of various sensors that detect microbe-specific components for recognizing the microbial invasion into the host. Distinct from other microbes such as bacteria and fungi, viruses are largely composed of host-derived materials, and do not contain their specific components, which are hardly distinguishable from host components. The host mechanism for sensing viruses evolved to focus on the detection of virus-derived genomes, which are composed of nucleic acids. Nucleic acid receptors may be classified into two types in terms of subcellular localization (Fig. 1): (1) membrane type and (2) cytosolic type. Essentially, each type of receptor contains either an RNA or DNA recognition motif. As a representative of membrane-type nucleic acid sensors, TLRs are a well-studied family of PRRs, currently comprised of at least thirteen members.

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Each TLR is known to distinctively recognize nucleic acids and/ or other molecules such as lipids and proteins derived from microbes. As for RNA recognition, TLR3 and TLR7/8 detect double-stranded RNA (ds-RNA) and single-stranded RNA (ssRNA), respectively [29,30]. On the other hand, TLR9 recognizes specific DNA sequences that contain unmethylated CpG motifs, which are commonly found in the genomes of infectious bacteria and viruses. The engagement of these TLRs with viral PAMPs results in the activation of intracellular signaling pathways mediated by IRFs and NF-κB, leading to the gene induction of type I IFNs, proinflammatory cytokines, chemokines and costimulatory molecules, involved in anti-microbial immunity. These four members (TLR3, TLR7, TLR8 and TLR9) of the TLR family are located in the membrane of intracellular compartments

Fig. 1. Two types of nucleic acid receptor in innate immunity. Nucleic acid receptors are classified into two types (upper panel): (1) membrane-associated receptors and (2) cytosolic receptors. For DNA sensors, TLR9 is the only known sensor that detects DNA in endosomes; cytosolic DNA sensors remained to be elucidated although there are two reports supporting the existence of the cytosolic DNA pathway [34,35]. DAI (DLM-1/ZBP1) has recently been identified as a candidate cytosolic DNA sensor, but the existence of other cytosolic DNA sensors (Dx) cannot be ruled out. It is as yet unknown what microbe are recognized by and whether or which adaptor protein (X1 or X2) interacts with DAI (DLM-1/ZBP1) or other unknown cytosolic DNA sensors (Dx). ds, double-stranded; ss, single-stranded; TRIF/TICAM1, TIRdomain-containing adaptor inducing IFN-β/TIR-containing adaptor molecule-1; 5'-ppp-ss-RNA, 5'-triphosphate single-stranded RNA; DAI, DNA-dependent activator of IRFs; ZBP1, Z-form DNA-binding protein 1; RIG-I, retinoic acid-inducible gene I; MDA5, melanoma-differentiation-associated gene 5; and TLR, Tolllike receptor; MAVS, mitochondrial antiviral signaling.

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such as endosomes. This coverage of the TLR recognition system is limited to microbes in the extracellular space. On the other hand, when microbes infect in the cytosolic space, viral genomic RNA is targeted by the cytosolic helicases, RIG-I and melanoma differentiation-associated gene 5 (MDA5) [36,38]. Although there have been major advancement in our understanding of cytosolic RNA recognition and its involvement in innate anti-viral responses [39], TLR9 has remained the only known sensor of foreign DNA until recently. In this regard, there have been several reports [34,35] supporting the existence of a cytosolic DNA pathway, leading to the activation of type I IFN genes. Shortly after the discovery of “interferon (IFN)” [11], it has been reported that genetic materials derived from either pathogens or hosts can induce the production of this IFN molecule in chicken and mouse fibroblasts [2,3,32]. More recently, it has been shown that this IFN response, i.e., type I IFN response, is also induced by synthetic DNAs and requires the kinases TBK1 and IKKi [34]. In addition to infection by viruses such as herpes simplex virus [40], infection by certain bacteria such as Listeria monocytogenes and Legionella pneumophila also activates the cytosolic DNA pathway, leading to type I IFN gene induction [35]. Importantly, the induction occurs in the absence of the TLR9 signaling pathway [34,35]. Thus, these reports “revisited’ the above original findings and strongly indicated in toto the existence of a DNA sensor(s) that functions independently of TLR9 signaling. 3. Identification of new DNA-sensing molecule, DAI (DLM-1/ZBP1) As has already been mentioned above, non-self nucleic acids from invading microbes or self nucleic acids exposed in a cell by infection or by incomplete clearance during cell damage, respectively evoke immune responses. In this context, RNA-sensing mechanisms have been extensively studied, while recent attention has focused on identifying and understanding DNA-sensing systems as they relate to protective and pathological immune responses. In addition to TLR9, the membrane receptor critical for the detection of immunostimulatory, typically unmethylated microbial DNA (CpG DNA), evidence indicates the presence of an uncharacterized cytosolic DNA sensor(s) that can also evoke innate immune responses. Indeed, double-stranded DNA endowed with the ability to enter the cytosol can stimulate TLR9-independent innate immune responses [41–43], the hallmark of which is the induction of type I IFN genes. Furthermore, accumulating evidence suggests the involvement of a cytosolic DNAsensing system in the development of autoimmunity [44–47]. During the course of our study by DNA chip analysis of IFNβ-treated Stat1-deficient mouse embryonic fibroblasts (MEFs), a gene previously termed DLM-1 or Zbp1 [37,48,49] whose product contains DNA-binding domains [49] was found to be IFN-inducible. Interestingly, in addition to Ddx58 and Ifih1 for the known cytosolic nucleic acid sensors RIG-I and MDA5, respectively, Zbp1 gene is listed among the top ten most remarkably induced genes in these cells [37]. It has found that the protein encoded by this gene interacts with DNA, leading to the activation of IRF-family transcriptional factors for type I

IFN gene induction. Therefore, the new name “DAI (DNAdependent activator of IRFs)” was proposed for this protein to better represent its function. This gene for DAI was first cloned by differential display, as DLM-1, which is highly upregulated in the peritoneal lining tissue of mice bearing ascites tumor [48]. This was followed by the finding that this protein contains two binding domains for left-handed Z-form DNA (Z-DNA), termed Zα and Zβ in the N-terminal region [49], and it is also reported that a region homologous to the Zα domain was found in the vaccinia virus (VV)-derived protein, E3L, which is essential for virus evasion [50]. On the other hand, the C-terminal region shows no homology to any known structure and has remained functionally undefined. From these previous findings, DLM-1/ZBP1 may play a potential role in host defense, but its biological function remains to be understood. DLM-1 mRNA is expressed in various tissues including spleen, thymus, liver, lung and heart [48]. Further study [48] revealed that DLM-1 is upregulated not only in tumor stromal cells but also in macrophages upon stimulation with type II IFN (IFN-γ). This gene can also be induced by treatment with type I IFNs (IFN-α/β) [37]. Consistent with these results, a database search [37] revealed that each typical sequence of the IFNstimulated gene responsive element (ISRE) as well as the IFN-γactivated site (GAS) is within the 5' promoter region of DLM-1. DAI (DLM-1/ZBP1) mRNA expression is also regulated by signaling triggered by PAMPs such as B-form DNA (B-DNA), IFN-stimulatory DNA (ISD) [35] and lipopolysaccharides (LPS) [48]. When B-DNA or ISD is delivered into the cytoplasm by transfection with lipofectamine reagent, DAI (DLM-1/ZBP1) mRNA is upregulated in wild-type MEFs; however, this induction is abolished in type I IFN-receptor (IFNAR-1)-deficient MEFs. This indicates that the upregulation of DAI (DLM-1/ ZBP1) mRNA by cytosolic DNA can occur through IFN-α/β signaling, which is induced upon DNA sensing. Therefore, similarly to the various genes involved in the induction of IFN responses, including the Ddx58 and Ifih1 genes that encode cytosolic RNA sensors for triggering the innate immune system, DAI (DLM-1/ZBP1) gene are IFN-inducible, perhaps to ensure the activation of robust innate immune response by positive feedback regulation. Consistent with its possible function as a sensor for cytosolic DNA, DAI (DLM-1/ZBP1) mainly localizes in the cytoplasm of cells with a diffuse but partially granular-like pattern [37]. Indeed, the granular formation of this protein in the cytoplasm was also previously reported: ZBP1 localizes in stress granules when cells are exposed to stresses such as heat shock and arsenite exposure [51]. DAI (DLM-1/ZBP1) co-localizes with transfected DNA in granules, which, however, these granules localize in the vicinity of the endoplasmic reticulum, but do not merged with any marker of intracellular organelles (Y. Ohba, unpublished observation). Is there any specific intracellular compartment for cytosolic DNA recognition? It is predicted that a autophagosome or an aggresome [52] may provide a site for cytosolic DNA recognition, because it has gradually been clarified that autophagy plays an important role not only in the elimination of certain intracellular bacteria (e.g., Shigella

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flexneri, Mycobacterium tuberculosis, and group A Streptococcus) [53–55], but also in anti-viral immune responses or virus replication (e.g., herpes virus and Sindbis virus) [56,57]. In this respect, it is interesting that the autophagic process is required for viral recognition in the innate immune system: Plasmacytoid dendritic cells (pDCs) can produce type I IFN in response to ssRNA viruses, through the autophagic process by which virusderived cytosolic ss-RNAs serve as pathogen signatures recognized by TLR7 [58,59]. However, the Atg5–Atg12 conjugate, a key component of the autophagic machinery, interacts with the cytosolic RNA sensor RIG-I and its adaptor IFN-β promoter stimulator 1 (IPS-1), resulting in the inhibition of the type I IFN production pathway [60]. Thus, it is an interesting future issue to determine whether the autophagic process is involved in cytosolic DNA recognition. 4. Signaling pathways downstream of DAI (DLM-1/ZBP1) 4.1. IRF pathway Recent extensive studies revealed that most IRF-family transcriptional factors function as crucial regulators for the PRRmediated gene induction of not only type I IFNs but also inflammatory cytokines [21,24,25,61]. As in a previous study [35], IFN-β induction by cytosolic DNA is severely suppressed in IRF-3-deficient MEFs (Fig. 2) [37]. In addition, a similar impairment in IFN-α4 mRNA induction in these mutant MEFs is also observed [37]. On the other hand, IRF-7-deficient MEFs can normally induce IFN-β mRNA in response to cytosolic DNA although a partial impairment in IFN-α4 mRNA induction was observed. These findings suggest that IRF-3 is a major transcriptional factor to induce type I IFN genes in response to cytosolic DNA, whereas IRF-7 partially cooperates with IRF-3 in the induction of this IFN-α4 subtype; however, the involvement of these two IRFs in the induction of other IFN-α subtypes is not still clarified. In this respect, the type I IFN

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induction pathway triggered by cytosolic DNA appears to be distinct from the TLR9-mediated pathway activated by extracellular DNA, wherein IRF-7 is exclusively involved. Thus, the IRF-3-mediated type I IFN induction by cytosolic DNA may be regulated by a unique pathway. The small interfering RNA (siRNA)-mediated suppression of the expression of the newly identified DNA sensor DAI (DLM-1/ZBP1) resulted in a suppressed induction of type I IFN mRNA by cytosolic DNA. In addition, DNA-induced IRF-3 dimerization is suppressed in siRNA-DAI (DLM-1/ZBP1)-treated cells. These therefore suggest that DAI (DLM-1/ZBP1) regulates DNA-mediated IRF-3 activation for type I IFN gene induction. How is IRF-3 activated for type I IFN induction upon DNA sensing? IRF-3 is activated by B-DNA through the TBK1- and IKKi-dependent signaling pathway [34]. Moreover, DAI (DLM-1/ ZBP1) associates with both TBK1 and IRF-3 in a ligand-dependent manner (Fig. 2) [37]. However, one of their known adaptor molecules, TRIF/TICAM-1, is dispensable in this pathway, whereas another adaptor IPS-1 seems to be partly involved in the activation of the Ifnb1 promoter [34,62], although its contribution is not so remarkable. It remains unknown how IPS-1 is involved in DAI (DLM-1/ZBP1)-mediated signaling; it is speculated that other unknown adaptors contribute to this signaling. 4.2. NF-κB pathway Concerning NF-κB activation induced by cytosolic DNA, a substantial activation of transcription factor NF-κB independent of TBK1 and IKKi occurs when a synthetic DNA, termed BDNA, consisting of poly(dA-dT)•poly(dT-dA), is delivered intracellullarly. On the other hand, any detectable activation of NF-κB as well as MAP kinases was not observed upon delivery of another synthetic DNA, termed ISD [35], which is apparently shorter than B-DNA [34]. NF-κB activation is not detected until 120 min after B-DNA stimulation [37], which is in accordance with the latter study [35]. This delayed response of NF-κB,

Fig. 2. Putative model of cytosolic DNA pathway through DAI (DLM-1/ZBP1) (see text for details). TBK1, TANK-binding kinase 1; IRF-3, interferon regulatory factor 3.

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which occurs with B-DNA stimulation but not with ISD stimulation, may be due to a secondary response to some cytokines that can activate NF-κB. However, a longer time may be required for DNA ligands to be recognized by a cytosolic sensor after their intracellular delivery, as compared with that in the case of extracellular administration with ligands, such as LPS. Alternatively, the seemingly discrepant observations described above may arise from the use of different ligands; the former group uses poly(dA:dT)•poly(dT:dA) that preferentially takes on a B-form configuration, whereas the latter group uses ISD composed of synthetic 45-base oligodeoxynucleotides. In this regard, it is likely that these ligands are recognized by distinct receptors (see below). The knockdown of DAI (DLM-1/ZBP1) expression results in a significant inhibition of DNA-mediated NF-κB activation. Consistently, the induction of NF-κB targets such IL-6 and IκBα are also suppressed in siRNA-DAI (DLM-1/ZBP1)-expressing cells. Therefore, it is presumed that DAI (DLM-1/ZBP1)-mediated signaling leads to the activation of not only IRF-3/IRF-7 but also NF-κB for the subsequent induction of type I IFNs and proinflammatory cytokines, respectively (Fig. 2). In cooperation with NF-κB, MyD88-IRF-5 is involved in the regulation of PRRmediated production of proinflammatory cytokines [61]. However, the induction of IL-6 and TNF-α in response to cytosolic DNA is normal in MEFs deficient in IRF-5. This is consistent with the normal response of MyD88-deficient MEFs to cytosolic DNA [34,35]. It remains to be clarified how DAI (DLM-1/ZBP1) activates NF-κB pathway; whether IPS-1 regulates both IRF and NF-κB pathways. A search for any DAI (DLM-1/ZBP1)-interacting molecule may provide a key to resolving these issues. 5. What is the molecular basis of DAI (DLM-1/ZBP1) activation by DNA? What is the molecular basis of DAI (DLM-1/ZBP1) activation by DNA? Various DNAs, including synthetic B- or Z-form DNA, or bacterial, viral or mammalian DNA, activate DAI (DLM-1/ ZBP1), albeit with different efficiencies [37]. As reported in a previous study [34], double-stranded B-DNA is more potent activity in activating IFN-α/β than Z-DNA. In addition, DAI (DLM-1/ZBP1) seems to have a stronger preference for B-DNA than Z-DNA. In contrast to that of type I IFN genes, the induction of certain chemokines such as Cxcl10 and Ccl5, does not appear to be dependent on DNA configuration: These chemokine genes are also markedly induced by Z-DNA as well as B-DNA. Thus, DAI (DLM-1/ZBP1) and possibly other cytosolic DNA sensor(s) may recognize these two different types of DNA via distinct mechanisms, which subsequently activate different sets of downstream genes. Unlike those of the cytosolic RNA sensors RIG-I or MDA5, the expression of any DAI (DLM-1/ZBP1) mutant lacking either the Zα, Zβ or D3 domain cannot lead to spontaneous activation of its downstream signaling. This indicates that DAI (DLM-1/ ZBP1) activation is not regulated by a structural inhibition mechanism, by which RIG-I/MDA5 activity is regulated. As shown in Fig. 2, we conjecture that DAI (DLM-1/ZBP1) activation requires its molecular oligomerization induced by the

binding of multiple numbers of DAI (DLM-1/ZBP1) proteins to one DNA strand, so as to provide a scaffold for the recruitment of signaling mediators. The detailed activation mechanism is an interesting future issue to address. 6. Redundancy in the cytosolic DNA-sensing system Is DAI (DLM-1/ZBP1) the sole DNA sensor? There are several lines of evidence that indicate the presence of a redundant cytosolic DNA-sensing molecules. In cells in which DAI (DLM-1/ZBP1) expression was suppressed by siRNA, the induction of type I IFN gene was suppressed but not completely abolished, this was particularly notable in embryonic fibroblasts (Ref. [37]; T. Taniguchi, unpublished observation). In addition, type I IFN gene induction by ISD, originally observed in embryonic fibroblasts [35], was not observed in L929 murine fibroblasts that can respond to B-DNA for the such gene induction [37]. In relation to these observations, DNA-mediated activation of innate immune response was observed to be normal in mice deficient in the DAI gene, generated recently by Akira and his colleagues (S. Akira, Osaka University; personal communication). These observations therefore strongly indicate the presence of a redundant cytosolic DNA-sensing molecule(s). 7. Family related to DAI (DLM-1/ZBP1) DAI (DLM-1/ZBP1) carries two homologous domains, namely, Zα and Zβ, at its N-terminus, whereas the C-terminal half of DAI (DLM-1/ZBP1) has no similarity with any reported proteins (Fig. 3). The Zα domain was originally identified in an adenosine deaminase acting on RNA (ADAR1) [63,64]. Also, the region that is structurally related to the Zα domain, is also found in three other proteins: DLM-1 [49], a PKR-like kinase (PKZ; protein kinase containing Z-DNA-binding domains) found in zebrafish [65], and a VV-derived protein (E3L) [66]. Further study by Rich's group provided a structural basis of the Zα domain of DLM-1 or ADAR1 to interact with characteristic features of the left-handed helical Z-DNA backbone [49,67], despite the Zα domain belonging to the winged helix-turn-helix (HTH) family of domains, most of which are well-characterized as a B-DNA-binding motif [68]. Thus, Zα domain-containing proteins represent a subfamily with derivation from the canonical function of the winged HTH family. From our data and previous data [34,37] showing that B-DNA rather than Z-DNA is a potent activator of the cytosolic DNA recognition pathway, it appears unlikely that Zα family members are involved in this process. However, cellular proteins containing Zα domains bear a second homologous domain termed Zβ. The crystal structure of the Zβ domain of human ADAR1 revealed that the Zβ domain belongs to the winged HTH family, similarly to the Zα domain, but structure-based comparative analysis revealed that the conserved surface of the Zβ domain differs from that of the Zα domain, suggesting that the Zβ domain lacks the ability to bind to Z-DNA [69]. Together with our above-mentioned data, it is speculated that the Zβ and D3 domains (Fig. 3) of DAI (DLM-1/ZBP1) are critical regions for the recognition of DNA derived from viruses, bacteria and even hosts. Our preliminary

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of RNA editing by ADARs. In this regard, one can easily envisage that ADARs may regulate not only host cell function but also innate defense by editing cellular and pathogen-derived RNAs. In addition, it might be presumed that like DAI (DLM-1/ ZBP1), ADAR1, which also carries the Zα and Zβ domains, may function as a sensor of DNAs derived from viruses, bacteria and even hosts. There are at least three alternatively spliced members in this family; ADAR1, ADAR2 and ADAR3 [70]. As shown in Fig. 3, only ADAR1 contains Z-DNA-binding domains and is IFN-inducible, which suggest that the activities of these domains of ADAR1 contribute to innate immune response. Further studies will be required to clarify the role of ADAR1 in microbial infection. 7.2. PKZ Fig. 3. Domain models of related members of DAI (DLM-1/ZBP1). DAI (DLM1/ZBP1) is found only in mammals whereas ADAR1 is found even in Drosophila. PKZ is reported only in zebrafish and goldfish. E3L is a vaccinia virusderived protein. Both Zα and Zβ are Z-form DNA-binding domains (ZBDs) [91]. The carboxyl terminal half of DAI (DLM-1/ZBP1) shows no homology with previously known motifs, but this region has been shown to contain TBK1/ IRF-3-interacting domain (tentatively labeled as TID in this figure) and D3 domain (D3), which is a putative B-form DNA-binding domain [37]. ADAR1 has both ZBDs and ds-RNA binding domains (RBDs), whereas ADAR2 and ADAR3 have only RBDs. All ADAR-family members have an adenosine deaminase domain (deaminase). The kinase domain of PKZ is quite similar to that of PKR, and has a kinase activity for eukaryotic initiation factor 2α (eIF2α).

inspection by database analysis shows that no region homologous to the D3 domain in related or unrelated members. As for the possible roles of the Zβ domain, there is an interesting observation that the Zα domain tethered to the Zβ domain of ADAR1 binds to Z-DNA with sequence preference; however, the binding by only the Zα domain is sequence-independent and conformation-specific. This suggests that the Zβ domain has a preference to certain nucleotide sequences. Although detailed study is required to define the functional role of the Zβ domain of DAI (DLM-1/ZBP1), this hypothesis does not seem to be supported by our result that the DAI (DLM-1/ZBP1)-mediated discrimination of DNA is not likely to be sequence-specific. In another respect, the database analysis showed that domains structurally homologous to the conserved surface of the Zβ domain are found in SmtB, isoflavone O-methyltransferase, MarR and the histone acetyltransferase Esa1 [69]. It is quite interesting to presume that these bacterial proteins such as SmtB and MarR might interact with DAI (DLM-1/ZBP1) or ADARs through the Zβ domain. In fact, the domains of most of these proteins mediate the formation of homo- or hetero-dimer. It would also be interesting to examine whether DAI (DLM-1/ ZBP1) is activated through its dimer formation mediated by the Zβ domain upon stimulation with DNA. 7.1. ADARs ADARs bind to ds-RNA through its ds-RNA-binding domains to deaminate adenosine (A) to inosine (I) for RNA editing. ds-RNAs formed by inverted repeats of non-coding sequences such as introns and 3'-UTRs are common substrates

PKZ is constitutively expressed at low levels and is highly induced in response to stimulation with poly(rI:rC), which mimics viral ds-RNA [65]. PKZ is closely related to mammalian PKR (protein kinase, ds-RNA-dependent) and shows the same function as an eukaryotic initiation factor 2α (eIF2α) kinase. However, it remains unknown whether or how this protein functions in fish host anti-viral response through their Z-DNA-binding domains. 7.3. E3L What is the role of the Zα domain of DAI (DLM-1/ZBP1) in the activation of the DNA recognition pathway? It remains unclear whether the Zα domain participates in DNA sensing, because from the previously reported co-crystal structure of the Zα domain of DLM-1 with Z-DNA, we cannot rule out the inability of this domain to bind to B-DNA although its affinity to B-DNA is predicted to be much lower than that to Z-DNA [64,71,72]. Our unpublished data shows that DNA-mediated type I IFN induction is partially inhibited in L929 cells expressing the DAI (DLM-1/ZBP1) deletion mutant, which lacks only the Zα domain (our unpublished data). Detailed analysis will be needed to answer this question. It is also of great interest that the Zα domain is also found in E3L derived from VV [64], a doublestranded DNA virus that replicates in the cytoplasm of infected cells. E3L also contains a double-stranded RNA binding domain at the C-terminus. It plays an essential role in the pathogenesis of VV by blocking the interferon system at multiple levels [73]. Of note, IRF-3 phosphorylation and Ifnb1 induction are observed upon infection with VVonly in the absence of E3L [74]. This has been considered to be caused by a possible mechanism in which the ds-RNA domain of E3L mediates its binding to and the sequestration of ds-RNA, which is a potent activator of RIG-I/ MDA5 as well as of 2',5'OAS (2',5'oligoadenylate synthetase) and PKR, so as to evade the IFN induction and its action [73]. However, it remains unknown whether the Zα domain of E3L may participate in this blockade of the IFN system. In mice, the Z-DNA-binding activity of the N-terminal domain of E3L (Zα) is necessary for viral pathogenesis [75,76]. E3L can also potently inhibit ADAR1 deaminase enzymatic activity through the Zα domain as well as through the ds-RNA-binding domain of E3L [77]. In this regard, it may be presumed that DAI (DLM-

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1/ZBP1) is also targeted by E3L, which may thus inhibit the activation of the DAI (DLM-1/ZBP1)-mediated cytosolic DNA pathway. 8. Biological roles of cytosolic DNA recognition pathway in microbial infection The most interesting issue to resolve is which microbes are recognized by the DNA sensor DAI (DLM-1/ZBP1) and to what extent DAI (DLM-1/ZBP1) contributes to the activation of innate immune responses triggered by cytosolic DNA derived from infected microbes. Non-pDCs cell types including conventional dendritic cells (cDCs) and macrophages produce IFN-α in response to herpes simplex virus type 1 (HSV-1), and that this production occurs largely in a TLR9-independent manner [40]. In this context, the siRNA-mediated downregulation of DAI (DLM1/ZBP1) expression results in a significant suppression of Ifnb1 induction upon HSV-1 infection [37] albeit not complete abolition. This indicates that DAI (DLM-1/ZBP1) is essential for the HSV-1-triggered IFN-β induction, however, as mentioned above, it is likely that other DNA sensors are also involved in this induction. VV, another DNA virus, induces type I IFNs when the virus lacks E3l as mentioned above. Our data indicated that IFNβ induction by VV genomic DNA is mediated by DAI (DLM-1/ ZBP1) [37]. However, detailed studies with VV lacks only the Zα domain of E3L will further clarify the involvement of DAI (DLM1/ZBP1) in VV infection. In addition, it would also be interesting to examine whether retrovirus-derived DNA, which is generated during an infection cycle, can be sensed by DAI (DLM-1/ZBP1). Type I IFN activation can be evoked by intracellular infection by several bacteria, including L. monocytogenes [78], S. flexneri [79], enterophathogenic E. coli [79] and L. pneumophila [35]. The induction of IFN-β in Listeria-infected macrophages is mediated through a cytosolic DNA pathway, which is not dependent on MyD88, or TRIF/TICAM-1 (TIR domain-containing adaptor inducing IFN-β/TIR-containing adaptor molecule-1), or TRAM/TICAM-2 (TRIF-related adaptor molecule/TIR-containing adaptor molecule-2), RIP2 (receptor interacting protein 2), or TLR9 [35,80]. The entry of Listeria into cells by endocytosis is followed by its escape into the cytosol by means of the poreforming protein Listeriolysin O (LLO). The requirement of LLO for the induction of IFN-β mRNA upon Listeria infection [78] suggests that the intracytoplasmic space is the place for triggering the response, that is, for sensing Listeria-derived DNA for the subsequent initiation of type I IFN response. In this regard, DAI (DLM-1/ZBP1) may play a role in the cytosolic recognition of DNA derived from bacteria such as Listeria. If such is the case, another interesting question is posed: What is the role of DAI (DLM-1/ZBP1)-mediated type I IFN induction in bacterial infection? Interesting, note that IFNs have anti-bacterial activity that inhibits the growth and invasion of intracellular bacteria including Shigella, Salmonella [81], Legionella [35,82], Rickettsiae [83] and Chlamydiae [84]. In addition to such a cell-intrinsic action, it can be speculated that type I IFNs also show a non-cellautonomous action for enhancing anti-bacterial immunity, that is, the activation of natural killer cells for the elimination of

bacterium-infected cells. On the other hand, it has been shown that mice deficient in either the IFNAR-1 receptor subunit or IRF-3 are more resistant to L. monocytogenes infection [85,86]. These suggest that the IFN-β induction during L. monocytogenes intracytosolic growth enhances bacterial survival and promotes infection. In addition, IFN-α is significantly induced in the lungs of mice infected with a particular clinical isolate of M. tuberculosis, and treatment with IFN-α resulted in increased lung bacillary loads and even reduced survival rate [87]. These lines of evidence lend further support to the notion that bacteria have evolved an ability to trigger type I IFN response, by exploiting it, to overcome host defenses by an as-yet undetermined mechanism (s). Furthermore, type I IFN activities are not limited to viral or bacterial infection. IFN treatment can suppress the intracellular growth of even protozoans such as Toxoplasma gondii [88–90]. Regardless of the role of type I IFNs, it will be interesting to study how DAI (DLM-1/ZBP1) contributes to anti-bacterial responses. 9. Self or non-self recognition through cytosolic DNA recognition pathway and its possible association with autoimmune abnormalities How does DAI (DLM-1/ZBP1) distinguish microbial nonself DNA from host self DNA? Is there any mechanism for distinguishing microbial DNA from host DNA? Host DNA is normally compartmentalized in the nucleus; even during cell division with the disappearance of the nuclear membrane, DNA forms condensed, highly ordered structures in complex with histone proteins and other DNA-associated proteins, which may contribute to the sequestration of host DNA from cytosolic DNA sensors. Thus, the aberrant exposure of DNA in the cytosol en masse, be it mediated by infection by DNA viruses or the incomplete clearance of dying cells, may activate cytosolic sensors such as DAI (DLM-1/ZBP1). Although TLR9 recognizes unmethylated CpG motifs, which are present at relatively high frequencies in non-vertebrate, bacterial/viral DNA, it remains to be determined whether DAI (DLM-1/ZBP1) has a specific ligand-binding property. Provided that Z-DNA is an essential motif for interaction with DAI (DLM1/ZBP1), one possible mechanism for distinguishing microbial DNA from host DNA is presumed to be based on the Z-DNAbinding activity of DAI (DLM-1/ZBP1). It is known that Z-DNA is a transient left-handed conformation that is observed frequently in association with gene transcription [91]. Several DNA viruses such as poxviruses, initiate gene transcription in the cytosol, which results in the appearance of Z-DNA in the cytoplasm. Therefore, it is hypothesized that this may lead to specific activation of DAI (DLM-1/ZBP1) through its Z-DNA-binding domain(s). However, the effect of Z-DNA on the induction of type I IFNs is much less than that of B-DNA [34,37], and DAI (DLM-1/ZBP1) may contain putative B-DNA-binding region(s) [37]. Further detailed analyses are needed to clarify which conformation predominantly functions in DAI (DLM-1/ZBP1) activation, which may provide a key to resolving this issue. The recognition by DAI (DLM-1/ZBP1) seems to be less stringently regulated since it can respond not only to viral and bacterial DNA, but also to mammalian DNA. Given that there is little structural

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distinction between microbial and host DNAs, the pattern recognition system is supposed to be regulated in two aspects for the prevention of the aberrant activation of the sensor with self DNA: (1) both the sensor and self DNA should be separately compartmentalized to prevent encounter with each other, (2) aberrant self DNA should be rapidly eliminated by DNases [47]. The abrogation of these regulatory mechanisms may contribute to the formation of excessive inflammatory response and autoimmune abnormalities. For example, it has been documented that systemic autoimmunity is triggered in mice deficient in DNase I or II, each of which is essential for the elimination of self DNA from extracellular fluids and lysosomes, respectively [45,47]. In particular, the livers of DNase II-deficient mouse embryos contain numerous macrophages carrying undigested DNA, wherein IFNβ mRNA is expressed in a TLR9-independent manner [47]. Whether DAI (DLM-1/ZBP1) is involved in this process awaits further investigation. 10. Conclusions and future prospects In recent years, the cytosolic DNA recognition system has gradually been clarified, and the recent identification of the DNA sensor DAI (DLM-1/ZBP1) may contribute to a better understanding of downstream signaling pathways. The next step is to identify an adaptor(s) that links to either or both IRF and NF-κB pathways. In relation to this, it is also interesting to examine the involvement of TNF receptor-associated factor (TRAF) 6 and TRAF3, which are essential for the PRR-mediated activation of the NF-κB pathway and type I IFN pathway, respectively [29,92– 94]. It is crucial to generate and analyze knockout mice that can be used to reveal the role of DAI (DLM-1/ZBP1) in infections with various intracellular pathogens such as DNA viruses, bacteria and fungi. However, as mentioned above, it is essential to define a redundant cytosolic DNA sensor(s) and to further analyze their roles in association with DAI (DLM-1/ZBP1). It is also interesting to determine how DAI (DLM-1/ZBP1) and other possible cytosolic DNA sensor(s) contribute to the development of autoimmunity caused by the incomplete digestion of apoptotic DNA [47]. In this regard, the mutant mice are also useful to test the association of the cytosolic DNA pathway with autoimmune inflammatory diseases such as systemic lupus erythematodes (SLE) in mouse models. To control L. monocytogenes infection, it may be a useful approach to target the cytosolic DNA-triggered IFN pathway, which shows a deteriorating effect on Listeria infection. Finally, the development of specific inhibitors of the cytosolic DNA-mediated IFN pathway has therapeutic implications. Further detailed analyses of the cytosolic DNA pathway will provide a molecular basis for searching a new approach to therapies for infections and autoimmune diseases. Acknowledgements We would like to thank Messrs Wang, Choi, and Ban, Miss Lu, and Drs Yanai, Negishi, Miyagishi, Kodama, Honda, and Ohba for their tremendous support to the work described in this review. We also thank Dr. Akira for informing us of the unpublished observation regarding DAI-deficient mice, and Miss

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