IFN TLR TLR TLR. Toll-like receptor TLR. IFN Retinoic acid inducible gene-i RIG-I RIG-I RNA RIG-I RIG-I RIG-I

Transcription

1 58 2 pp RNA RIG-I RIG-I RIG-I RNA RNA IFN RIG-I RNA RIG-I RNA RNA RIG-I RNA RIG-I 1 2 Toll-like receptor TLR I TEL : FAX : sgo@virus.kyoto-u.ac.jp IFN IFN TLR TLR TLR IFN IFN Retinoic acid inducible gene-i RIG-I RNA IFN RNA RIG-I RIG-I RNA RNA RIG-I 2 RIG-I IFN

2 RIG-I MDA5 LGP2 RIG-I/MDA5 IPS-1 RIG-I N CARD 2 RNA C RD MDA5 RIG-I N CARD 2 RNA C RD LGP2 CARD RIG- I C RD IPS-1 N CARD Proline-rich region PRR C TMD IPS-1 TMD RNA double-stranded RNA; dsrna RIG-I dsrna 1 116kDa RNA RIG-I N Caspase recruitment domain CARD 2 DEXD/H RNA CARD RIG-I IFN CARD RIG-I IFN CARD RIG-I C Repressor domain RD 2 RD CARD aa CARD RIG-I RIG-I ATP CARD CARD CARD IFN- promoter stimulator-1 3 IPS-1 MAVS 4 VISA 5 Cardif 6 CARD TBK1 5 IKK-i 6 IKK IKK IKK IRF-3 IRF-7 NF- B CREB-binding protein CBP p300 IFN IFN IFN IFN JAK-STAT IFN IFNstimulated genes; ISGs ISGs RIG-I ISG IFN

3 pp RIG-I ATP CARD RIG-I IPS-1 CARD TBK1/IKK-i IKK /IKK /IKK IRF-3/IRF-7 NF- B CBP/p300 IFN IFN IFN JAK-STAT IFN RIG-I IPS-1 C Transmembrane domain TMD 4 IPS-1 3 RIG-I RIG-I 2 Melanoma differentiation-associated gene 5 MDA5 Laboratory of genetics and physiology 2 LGP2 RIG-I-like receptors RLRs 7 RIG-I MDA5 N CARD 2 RNA MDA5 RIG-I IFN MDA5 CARD ATP IPS-1 IFN MDA5 C RD 2 MDA5 LGP2 N C RD 2 CARD 7 LGP2 LGP2 RIG-I MDA5

4 RIG-I 5' ssrna dsrna ATP 3' dsrna RIG-I 5' dsrna RIG-I ATP Poly I:C RIG-I mrna rrna trna RNA 5' RIG-I RIG-I CTD Basic cleft RNA 7-10 LGP2 11 LGP2 RLRs IFN RIG-I MDA5 12 RIG-I MDA5 RNA RIG-I dsrna 5' RNA single stranded RNA; ssrna RIG-I RNA 5' mrna rrna trna RNA 5' RIG- I 5' RNA RNA 5' VPg RIG-I RIG-I

5 pp dsrna 5' ssrna MDA5 1kb dsrna 15 dsrna MDA5 RNA ds dsrna RIG-I MDA5 4 RIG-I RIG-I RNA RNA in vitro 16 dsrna RIG-I dsrna 5' ssrna RIG-I RIG-I ATPase RNA ATP RIG-I RIG-I K270A RIG-I dsrna 5' ssrna RIG-I RNA ATPase RIG-I RNA RIG-I 3' dsrna 5' dsrna RIG-I dsrna IFN RIG-I RIG-I IFN RNA 25bp dsrna RIG-I microrna dsrna RIG-I 5 RIG-I RNA RIG-I RNA RIG-I RNA 16 RIG-I RNA IFN RIG-I RNA RNA RIG-I RIG-I dsrna 5' ssrna 17kDa RIG-I Poly I:C 66kDa RNA RNA RIG-I 17kDa RIG-I C aa RD aa RIG-I C- terminal domain CTD CTD RIG-I RIG-I CTD RNA RIG-I RNA CTD RIG-I RNA CTD RNA RD NMR CTD CTD 9 4 Basic cleft Acidic patch 5' ssrna NMR NMR RNA Basic cleft RIG-I CTD Basic cleft RNA CTD X CTD 4 Zn RIG-I RNA 17 CTD RNA ATP RIG-I ATP RIG-I IFN

6 TLR RIG-I RIG-I 1 Yoneyama M, Mikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, Taira K, Akira S, Fujita T.: The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5: , Saito T, Hirai R, Loo YM, Owen D, Johnson CL, Sinha SC, Akira S, Fujita T, Gale M Jr.: Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2. Proc. Natl. Acad. Sci. USA. 104: , Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, Ishii KJ, Takeuchi O, Akira S.: IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat. Immunol. 6: , Seth RB, Sun L, Ea CK, Chen ZJ.: Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122: , Xu LG, Wang YY, Han KJ, Li LY, Zhai Z, Shu HB.: VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol. Cell 19: , Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, Tschopp J.: Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437: , Yoneyama M, Kikuchi M, Matsumoto K, Imaizumi T, Miyagishi M, Taira K, Foy E, Loo YM, Gale M Jr, Akira S, Yonehara S, Kato A, Fujita T.: Structural mechanism of RNA recognition by the RIG-I-like receptors. J. Immunol. 175: , Rothenfusser S, Goutagny N, DiPerna G, Gong M, Monks BG, Schoenemeyer A, Yamamoto M, Akira S, Fitzgerald KA.: The RNA helicase Lgp2 inhibits TLRindependent sensing of viral replication by retinoic acid-inducible gene-i. J. Immunol. 175: , Komuro A, Horvath CM. : RNA- and virus-independent inhibition of antiviral signaling by RNA helicase LGP2. J. Virol. 80: , Murali A, Li X, Ranjith-Kumar CT, Bhardwaj K, Holzenburg A, Li P, Kao CC. : Structure and function of LGP2, a DEX(D/H) helicase that regulates the innate immunity response. J. Biol. Chem. 283: , Venkataraman T, Valdes M, Elsby R, Kakuta S, Caceres G, Saijo S, Iwakura Y, Barber GN.: Loss of DExD/H box RNA helicase LGP2 manifests disparate antiviral responses. J. Immunol. 178: , Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ, Yamaguchi O, Otsu K, Tsujimura T, Koh CS, Reis e Sousa C, Matsuura Y, Fujita T, Akira S.: Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 411: , Hornung V, Ellegast J, Kim S, Brzózka K, Jung A, Kato H, Poeck H, Akira S, Conzelmann KK, Schlee M, Endres S, Hartmann G.: 5'-Triphosphate RNA is the ligand for RIG-I. Science 314: , Pichlmair A, Schulz O, Tan CP, Näslund TI, Liljeström P, Weber F, Reis e Sousa C.: RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates. Science 314: , Kato H, Takeuchi O, Mikamo-Satoh E, Hirai R, Kawai T, Matsushita K, Hiiragi A, Dermody TS, Fujita T, Akira S.: Length-dependent recognition of doublestranded ribonucleic acids by retinoic acid-inducible gene-i and melanoma differentiation-associated gene 5. J. Exp. Med. 205: , Takahasi K, Yoneyama M, Nishihori T, Hirai R, Kumeta H, Narita R, Gale M Jr, Inagaki F, Fujita T.: Nonself RNA-sensing mechanism of RIG-I helicase and activation of antiviral immune responses. Mol. Cell 29: , Cui S, Eisenächer K, Kirchhofer A, Brzózka K, Lammens A, Lammens K, Fujita T, Conzelmann KK, Krug A, Hopfner KP.: The C-terminal regulatory domain is the RNA 5'-triphosphate sensor of RIG-I. Mol. Cell 29: , 2008

7 pp Structural and Functional Views of the Intracellular Viral RNA Sensor RIG-I Seigyoku GO 1,2), Mitsutoshi YONEYAMA 1,2,3), Takashi FUJITA 1,2) 1 Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University 2 Laboratory of Molecular Cell Biology, Graduate School of Biostudies, Kyoto University 3 PRESTO, Japan Science and Technology Agency The innate immunity plays a crucial role in initial response to viral infection. Retinoic acid inducible gene-i (RIG-I) detects diverse viral RNAs in host cell and triggers immune response, producing antiviral cytokine, namely type I interferon (IFN). Recently, we analyzed the substrate RNAs and identified RNA binding domain of RIG-I. Here we discuss structural mechanism of intracellular RNA sensing system by RIG-I and function of RIG-I family molecules in the antiviral innate immunity.

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