| Structural highlights
Disease
RIGI_HUMAN Singleton-Merten dysplasia. The disease is caused by variants affecting the gene represented in this entry.
Function
RIGI_HUMAN Innate immune receptor that senses cytoplasmic viral nucleic acids and activates a downstream signaling cascade leading to the production of type I interferons and pro-inflammatory cytokines (PubMed:15208624, PubMed:16125763, PubMed:15708988, PubMed:16127453, PubMed:16153868, PubMed:17190814, PubMed:18636086, PubMed:19122199, PubMed:19211564, PubMed:29117565, PubMed:28469175, PubMed:31006531, PubMed:34935440). Forms a ribonucleoprotein complex with viral RNAs on which it homooligomerizes to form filaments (PubMed:15208624, PubMed:15708988). The homooligomerization allows the recruitment of RNF135 an E3 ubiquitin-protein ligase that activates and amplifies the RIG-I-mediated antiviral signaling in an RNA length-dependent manner through ubiquitination-dependent and -independent mechanisms (PubMed:28469175, PubMed:31006531). Upon activation, associates with mitochondria antiviral signaling protein (MAVS/IPS1) that activates the IKK-related kinases TBK1 and IKBKE which in turn phosphorylate the interferon regulatory factors IRF3 and IRF7, activating transcription of antiviral immunological genes including the IFN-alpha and IFN-beta interferons (PubMed:28469175, PubMed:31006531). Ligands include 5'-triphosphorylated ssRNAs and dsRNAs but also short dsRNAs (<1 kb in length) (PubMed:15208624, PubMed:15708988, PubMed:19576794, PubMed:19609254, PubMed:21742966). In addition to the 5'-triphosphate moiety, blunt-end base pairing at the 5'-end of the RNA is very essential (PubMed:15208624, PubMed:15708988, PubMed:19576794, PubMed:19609254, PubMed:21742966). Overhangs at the non-triphosphorylated end of the dsRNA RNA have no major impact on its activity (PubMed:15208624, PubMed:15708988, PubMed:19576794, PubMed:19609254, PubMed:21742966). A 3'overhang at the 5'triphosphate end decreases and any 5'overhang at the 5' triphosphate end abolishes its activity (PubMed:15208624, PubMed:15708988, PubMed:19576794, PubMed:19609254, PubMed:21742966). Detects both positive and negative strand RNA viruses including members of the families Paramyxoviridae: Human respiratory syncytial virus and measles virus (MeV), Rhabdoviridae: vesicular stomatitis virus (VSV), Orthomyxoviridae: influenza A and B virus, Flaviviridae: Japanese encephalitis virus (JEV), hepatitis C virus (HCV), dengue virus (DENV) and west Nile virus (WNV) (PubMed:21616437, PubMed:21884169). It also detects rotaviruses and reoviruses (PubMed:21616437, PubMed:21884169). Detects and binds to SARS-CoV-2 RNAs which is inhibited by m6A RNA modifications (Ref.66). Also involved in antiviral signaling in response to viruses containing a dsDNA genome such as Epstein-Barr virus (EBV) (PubMed:19631370). Detects dsRNA produced from non-self dsDNA by RNA polymerase III, such as Epstein-Barr virus-encoded RNAs (EBERs). May play important roles in granulocyte production and differentiation, bacterial phagocytosis and in the regulation of cell migration.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]
Publication Abstract from PubMed
RIG-I activates interferon signaling pathways by promoting filament formation of the adaptor molecule, MAVS. Assembly of the MAVS filament is mediated by its CARD domain (CARDMAVS), and requires its interaction with the tandem CARDs of RIG-I (2CARDRIG-I). However, the precise nature of the interaction between 2CARDRIG-I and CARDMAVS, and how this interaction leads to CARDMAVS filament assembly, has been unclear. Here we report a 3.6 A electron microscopy structure of the CARDMAVS filament and a 3.4 A crystal structure of the 2CARDRIG-I:CARDMAVS complex, representing 2CARDRIG-I "caught in the act" of nucleating the CARDMAVS filament. These structures, together with functional analyses, show that 2CARDRIG-I acts as a template for the CARDMAVS filament assembly, by forming a helical tetrameric structure and recruiting CARDMAVS along its helical trajectory. Our work thus reveals that signal activation by RIG-I occurs by imprinting its helical assembly architecture on MAVS, a previously uncharacterized mechanism of signal transmission.
Molecular Imprinting as a Signal-Activation Mechanism of the Viral RNA Sensor RIG-I.,Wu B, Peisley A, Tetrault D, Li Z, Egelman EH, Magor KE, Walz T, Penczek PA, Hur S Mol Cell. 2014 Jul 9. pii: S1097-2765(14)00492-4. doi:, 10.1016/j.molcel.2014.06.010. PMID:25018021[21]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Yoneyama M, Kikuchi 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. 2004 Jul;5(7):730-7. Epub 2004 Jun 20. PMID:15208624 doi:10.1038/ni1087
- ↑ Sumpter R Jr, Loo YM, Foy E, Li K, Yoneyama M, Fujita T, Lemon SM, Gale M Jr. Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I. J Virol. 2005 Mar;79(5):2689-99. PMID:15708988 doi:10.1128/JVI.79.5.2689-2699.2005
- ↑ 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. 2005 Sep 9;122(5):669-82. PMID:16125763 doi:10.1016/j.cell.2005.08.012
- ↑ 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. 2005 Oct;6(10):981-8. Epub 2005 Aug 28. PMID:16127453 doi:10.1038/ni1243
- ↑ 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. 2005 Sep 16;19(6):727-40. PMID:16153868 doi:S1097-2765(05)01556-X
- ↑ 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 U S A. 2007 Jan 9;104(2):582-7. Epub 2006 Dec 26. PMID:17190814 doi:0606699104
- ↑ Friedman CS, O'Donnell MA, Legarda-Addison D, Ng A, Cardenas WB, Yount JS, Moran TM, Basler CF, Komuro A, Horvath CM, Xavier R, Ting AT. The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response. EMBO Rep. 2008 Sep;9(9):930-6. doi: 10.1038/embor.2008.136. Epub 2008 Jul 18. PMID:18636086 doi:10.1038/embor.2008.136
- ↑ Mukherjee A, Morosky SA, Shen L, Weber CR, Turner JR, Kim KS, Wang T, Coyne CB. Retinoic acid-induced gene-1 (RIG-I) associates with the actin cytoskeleton via caspase activation and recruitment domain-dependent interactions. J Biol Chem. 2009 Mar 6;284(10):6486-94. doi: 10.1074/jbc.M807547200. Epub 2009, Jan 3. PMID:19122199 doi:10.1074/jbc.M807547200
- ↑ Bamming D, Horvath CM. Regulation of signal transduction by enzymatically inactive antiviral RNA helicase proteins MDA5, RIG-I, and LGP2. J Biol Chem. 2009 Apr 10;284(15):9700-12. doi: 10.1074/jbc.M807365200. Epub 2009 , Feb 11. PMID:19211564 doi:10.1074/jbc.M807365200
- ↑ Schlee M, Roth A, Hornung V, Hagmann CA, Wimmenauer V, Barchet W, Coch C, Janke M, Mihailovic A, Wardle G, Juranek S, Kato H, Kawai T, Poeck H, Fitzgerald KA, Takeuchi O, Akira S, Tuschl T, Latz E, Ludwig J, Hartmann G. Recognition of 5' triphosphate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus. Immunity. 2009 Jul 17;31(1):25-34. doi: 10.1016/j.immuni.2009.05.008. Epub 2009, Jul 2. PMID:19576794 doi:10.1016/j.immuni.2009.05.008
- ↑ Ablasser A, Bauernfeind F, Hartmann G, Latz E, Fitzgerald KA, Hornung V. RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate. Nat Immunol. 2009 Oct;10(10):1065-72. doi: 10.1038/ni.1779. Epub 2009 Jul 16. PMID:19609254 doi:10.1038/ni.1779
- ↑ Chiu YH, Macmillan JB, Chen ZJ. RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell. 2009 Aug 7;138(3):576-91. doi: 10.1016/j.cell.2009.06.015. Epub 2009 Jul, 23. PMID:19631370 doi:10.1016/j.cell.2009.06.015
- ↑ Jiang M, Osterlund P, Sarin LP, Poranen MM, Bamford DH, Guo D, Julkunen I. Innate immune responses in human monocyte-derived dendritic cells are highly dependent on the size and the 5' phosphorylation of RNA molecules. J Immunol. 2011 Aug 15;187(4):1713-21. doi: 10.4049/jimmunol.1100361. Epub 2011, Jul 8. PMID:21742966 doi:10.4049/jimmunol.1100361
- ↑ Shi Y, Yuan B, Zhu W, Zhang R, Li L, Hao X, Chen S, Hou F. Ube2D3 and Ube2N are essential for RIG-I-mediated MAVS aggregation in antiviral innate immunity. Nat Commun. 2017 May 4;8:15138. doi: 10.1038/ncomms15138. PMID:28469175 doi:https://dx.doi.org/10.1038/ncomms15138
- ↑ Zhao C, Jia M, Song H, Yu Z, Wang W, Li Q, Zhang L, Zhao W, Cao X. The E3 Ubiquitin Ligase TRIM40 Attenuates Antiviral Immune Responses by Targeting MDA5 and RIG-I. Cell Rep. 2017 Nov 7;21(6):1613-1623. doi: 10.1016/j.celrep.2017.10.020. PMID:29117565 doi:https://dx.doi.org/10.1016/j.celrep.2017.10.020
- ↑ Cadena C, Ahmad S, Xavier A, Willemsen J, Park S, Park JW, Oh SW, Fujita T, Hou F, Binder M, Hur S. Ubiquitin-Dependent and -Independent Roles of E3 Ligase RIPLET in Innate Immunity. Cell. 2019 May 16;177(5):1187-1200.e16. doi: 10.1016/j.cell.2019.03.017. Epub , 2019 Apr 18. PMID:31006531 doi:https://dx.doi.org/10.1016/j.cell.2019.03.017
- ↑ van Gent M, Chiang JJ, Muppala S, Chiang C, Azab W, Kattenhorn L, Knipe DM, Osterrieder N, Gack MU. The US3 Kinase of Herpes Simplex Virus Phosphorylates the RNA Sensor RIG-I To Suppress Innate Immunity. J Virol. 2022 Feb 23;96(4):e0151021. doi: 10.1128/JVI.01510-21. Epub 2021 Dec 22. PMID:34935440 doi:https://dx.doi.org/10.1128/JVI.01510-21
- ↑ Bechtel S, Rosenfelder H, Duda A, Schmidt CP, Ernst U, Wellenreuther R, Mehrle A, Schuster C, Bahr A, Blocker H, Heubner D, Hoerlein A, Michel G, Wedler H, Kohrer K, Ottenwalder B, Poustka A, Wiemann S, Schupp I. The full-ORF clone resource of the German cDNA Consortium. BMC Genomics. 2007 Oct 31;8:399. PMID:17974005 doi:https://dx.doi.org/1471-2164-8-399
- ↑ Loo YM, Gale M Jr. Immune signaling by RIG-I-like receptors. Immunity. 2011 May 27;34(5):680-92. doi: 10.1016/j.immuni.2011.05.003. PMID:21616437 doi:https://dx.doi.org/10.1016/j.immuni.2011.05.003
- ↑ Kato H, Takahasi K, Fujita T. RIG-I-like receptors: cytoplasmic sensors for non-self RNA. Immunol Rev. 2011 Sep;243(1):91-8. doi: 10.1111/j.1600-065X.2011.01052.x. PMID:21884169 doi:https://dx.doi.org/10.1111/j.1600-065X.2011.01052.x
- ↑ Wu B, Peisley A, Tetrault D, Li Z, Egelman EH, Magor KE, Walz T, Penczek PA, Hur S. Molecular Imprinting as a Signal-Activation Mechanism of the Viral RNA Sensor RIG-I. Mol Cell. 2014 Jul 9. pii: S1097-2765(14)00492-4. doi:, 10.1016/j.molcel.2014.06.010. PMID:25018021 doi:https://dx.doi.org/10.1016/j.molcel.2014.06.010
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