Toll-like receptor (TLR) 7. Viperin. Viperin. TLR7/9 Interferon regulatory factor (IRF) 7 IRAK1 K63. Pathogen-associated molecular.

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1 62 1 pp DNA RNA I DNA TRIM56 TRIM56 K63 TBK1 I DNA TRIM56 Toll-like receptor (TLR) 7 TLR9 I Viperin TLR7/9 I Viperin TLR7/9 Interferon regulatory factor (IRF) 7 Viperin TLR7/9 IRF7 TRAF6 IRAK1 IRAK1 K63 IRAK1 IRF7 I Viperin TLR7/9 I F TEL: FAX: sakira@biken.osaka-u.ac.jp Pathogen-associated molecular patterns: PAMPs Patternrecognition receptors: PRRs PRRs PRRs Toll-like receptor TLR) 1) TLR PAMPs TLR IL-1 TIR TLR MyD88 TRIF

2 エンドソーム DNA ppp-dsrna Pol III dsdna MyD88 TLR9 RIG-I DNA センサー (DAI, IFI16, DDX41) AIM2 インフラマゾーム AIM2 ASC IPS-1 Caspase-1 TBK1 Pro-IL-1 IRF7 IRF3 IL-1 I 型インターフェロン 1 DNA DNA PRR TLR9 RIG-I AIM2 DAI DNA TLR9 DNA MyD88 IRF7 I RIG-I RNA III 5 (5 -PPP) RNA IPS-1 TBK1 IRF3 I AIM2 DNA Caspase-1 Pro-IL-1 IL-1 I DNA DAI DNA DNA I TBK1 IRF3 NF- B IRF 1 TLR7 TLR9 1 MyD88 IRF7 MyD88 IRF7 2 1 PAMPs PRR RIG-I-like receptor RLR) NOD-like receptor NLR) 2) RLR RNA I (IFN) NLR NLRP3) Caspase-1 IL-1 TLR RLR NLR C RLR NLR TLR 2. DNA DNA DNA I IFN 3) TLR9 DNA I 1,2 DNA 1,2) DNA TLR9 DNA RNA III RNA 5 RIG-I 4) DNA PRR

3 pp dsdna 刺激 TRIM56 RING Coiled-coil B-box 734 aa TRIM56 Ub Ub Ub TBK1 Ub P TBK1 Ub P P IRF3 I 型インターフェロン 2 TRIM56 TRIM56 K63 TBK1 TBK1 IRF3 I DAI AIM2 DAI DNA I IFN DNA 5,6) AIM2 ASC Caspase-1 AIM2 I IL-1 7) DNA I IFN TBK1 IRF3 IRF3 IFN DNA TBK1 8) IFN ISRE B DNA[poly da:dt) poly dt:da)] HSV-1DNA I DNA 9) DNA 3. TRIM56 DNA HEK293 cdna IFN B DNA TRIM(tripartite motif) TRIM56 10) TRIM 60 RING E3 TRIM56 DNA I TRIM56 I TRIM56 IFN TRIM56 K 63 TRIM K150R K150R TBK1 TRIM56 TBK1 in vitro TRIM56 DNA TRIM56 DNA

4 DNA virus ssdna CpG Endosome ssdna CpG Lysosome TLR9 IRAK4 MyD88 TRAF6 TLR9 IRAK4 MyD88 TRAF3 Lipid droplet Viperin IκB kinase complex IRAK1 IRF7 kinase TRAF6 Ub E3 ligase IκBα RelA Transcription factor Transcription factor IRF7 K63-linked Ubiquitination Cytosol RelA Nuclear translocation Nuclear translocation IRF7 Nucleus Transcriptional activation Transcriptional Activation Inflammatory cytokines Type I IFN IFN-inducible genes 3 TLR9. CpG DNA TLR9 DNA TLR9 MyD88-IRAK4-TRAF6 I B kinase I B RelA/p65 RelA/p65 NF- B DNA TLR9 MyD88-IRAK4- IRAK1-TRAF6 IRF7 IRF7 IRF7 I Viperin TRAF6 IRAK1 K63 IRAK1 TRAF6 DNA 9) TBK1 -TBK1 IRF3 TRIM56 DNA dot dot DNA K150R TBK1 TBK1 TBK1 TBK1 TRIM56 DNA RLR RNA RLR IPS-1 :MAVS VISA Cardif TRIM56 IPS-1 IPS-1 RLR TRIM56 IPS-1 4. Viperin 1 TLR7 RIG-I IRF7 I

5 pp Viperin RSAD2 11 Viperin C 12,13 Viperin N 14 Radical S-adenosylmethionine SAM) Viperin Viperin I TLR3/4/9 RLR IRF3 IRF7 I Viperin Viperin 5. Viperin Viperin Viperin Viperin TLR7/9 I TLR7/9 RNA RLR DNA I Viperin TLR2/4 Nodlike receptor(nlr) Viperin Viperin TLR7/9 I 6. TLR7/9 1 Viperin TLR7/9 I Viperin Viprin B220 CD11c ( ) Viperin TLR7/9 I MyD88 IRAK4 IRAK1 TRAF6 IRF7 Viperin Viperin TRAF6 IRAK1 TRAF6 TLR Tumor necrosis factor receptor RING K63 IRAK1 TLR TRAF6 IRF7 TLR7/9 I TRAF6 IRAK1 K63 Viperin IRAK1 K63 Viperin TLR9 IRAK1 K63 K134 K180 R IRAK1 K63 TLR9 I Viperin TRAF6 IRAK1 K63 I ) Viperin N Viperin Viperin Viperin TRAF6 IRAK1 Viperin Viperin TRAF6 IRAK1 IRAK1 IRF7 Viperin I TLR9 I

6 TLR9 Viperin TRAF6 IRAK1 TRIM56 DNA DNA DNA DNA DNA DNA DMXAA Viperin Viperin N Radical SAM Viperin Radical SAM Viperin 15) Viperin 1 Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol, 11, (2010) 2 Kawai T, Akira S. The roles of TLRs, RLRs and NLRs in pathogen recognition. Int Immunol. 21, (2009) 3 Ishii KJ, Coban C, Kato H, et al.: A Toll-like receptor- independent antiviral response induced by doublestranded B-form DNA. Nat Immunol, 7, 40-8 (2006) 4 Chiu YH, Macmillan JB, Chen ZJ.: RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell, 138, (2009) 5 Yanai H, Savitsky D, Tamura T, et al.: Regulation of the cytosolic DNA-sensing system in innate immunity: a current view. Curr Opin Immunol. 21, (2009) 6 Ishii KJ, Kawagoe T, Koyama S, et al.: TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines. Nature, 451, (2008) 7 Bauernfeind F, Ablasser A, Bartok E et al.: Inflammasomes: current understanding and open questions. Cell Mol Life Sci [Epub ahead of print] 8 Ishikawa H, Ma Z, Barber GN.: regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature, 461, (2009) 9 Ishikawa H, Barber GN. is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature, 455,674-8 ( Tsuchida T, Zou J, Saitoh T, Kumar H, Abe T, Matsuura Y, Kawai T, Akira S. The ubiquitin ligase TRIM56 regulates innate immune responses to intracellular double-stranded DNA. Immunity : Saitoh T, Satoh T, Yamamoto N, Uematsu S, Takeuchi O, Kawai T, Akira S.Antiviral protein Viperin promotes Toll-like receptor 7- and Toll-like receptor 9-mediated type I interferon production in plasmacytoid dendritic cells. Immunity : Fitzgerald KA. The interferon inducible gene: Viperin. J Interferon Cytokine Res : Jiang D, Guo H, Xu C, Chang J, Gu B, Wang L, Block TM, Guo JT. Identification of three interferon-inducible cellular enzymes that inhibit the replication of hepatitis C virus. J Virol : Hinson ER, Cresswell P. Proc Natl Acad Sci U S A. The antiviral protein, viperin, localizes to lipid droplets via its N-terminal amphipathic alpha-helix : Duschene KS, Broderick JB. The antiviral protein viperin is a radical SAM enzyme. FEBS Lett :

7 pp Nucleic acids recognition by innate immunity Shizuo AKIRA, Tatsuya SAITOH, Taro KAWAI Laboratory of Host Defense, WPI Immunology Frontier Research Center(IFReC), Osaka University Department of Host Defense, Research Institute for Microbial Diseases The innate immune system detects pathogen-derived nucleic acids (DNA and RNA) and induces type I interferon (IFN) and other cytokines, resulting in the host defense against pathogen. We identified interferon-inducible tripartite-motif (TRIM) 56 as a regulator of double-stranded DNAmediated type I interferon induction. TRIM56 interacted with and targeted it for lysine 63-linked ubiquitination. This modification induced dimerization, which was a prerequisite for recruitment of the antiviral kinase TBK1 and subsequent induction of IFN-. Taken together, these results show that TRIM56 is an interferon-inducible E3 ubiquitin ligase that modulates to confer double-stranded DNA-mediated innate immune responses. It is well known that Toll-like receptor 7 (TLR7) and TLR9 sense viral nucleic acids and induce production of type I interferon (IFN) by plasmacytoid dendritic cells (pdcs) to protect the host from virus infection. We showed that the IFN-inducible antiviral protein Viperin promoted TLR7- and TLR9-mediated production of type I IFN by pdcs. Viperin expression was potently induced after TLR7 or TLR9 stimulation and Viperin localized to the cytoplasmic lipid-enriched compartments, lipid bodies, in pdcs. Viperin interacted with the signal mediators IRAK1 and TRAF6 to recruit them to the lipid bodies and facilitated K63-linked ubiquitination of IRAK1 to induce the nuclear translocation of transcription factor IRF7. Thus, besides direct inhibition of viral replication, this finding reveals that Viperin mediates its antiviral function via the regulation of the TLR7 and TLR9-IRAK1 signaling axis in pdcs.

8 pp