RIG‐I‐Like Receptors

Hui Yee Yong, Nanyang Technological University, Singapore
Dahai Luo, Nanyang Technological University, Singapore

Published online: November 2015

DOI: 10.1002/9780470015902.a0026237

Abstract

The RIG‐I‐like receptors (RLRs), RIG‐I (retinoic acid inducible gene 1), MDA5 (melanoma differentiation‐associated gene 5) and LGP2 (laboratory of genetics and physiology 2) play an essential role in sensing viral infection and initiating interferon‐mediated antiviral immune response. RLRs share similar domain architecture to support specific detection of viral RNA (ribonucleic acid). RIG‐I has an auto‐inhibitory conformation and upon binding of RNA ligand undergoes conformational changes to expose N‐terminal CARDs (caspase activation and recruitment domains) for interaction with the adaptor protein MAVS (mitochondrial antiviral‐signalling protein) for signalling. MDA5 adopts an open but inactive conformation and is able to oligomerise on long RNA duplexes to bring its CARDs into close proximity to MAVS. The downstream signalling cascade up‐regulates the type I interferon expression. Post‐translational modifications, alternative splicing and translational variants as well as several regulatory proteins play important roles in the regulation of RLRs signalling. Although robust activation of RLRs is essential for clearance of viral infection, uncontrolled activation of RLR signalling could potentially trigger or exacerbate pre‐existing autoimmune conditions.

Key Concepts

  • RIG‐I‐like receptors (RLRs) are pattern recognition receptor (PRR) which specifically recognise viral RNAs
  • RLRs undergo conformational changes leading to activation when bound to viral RNA
  • RLRs relay signal to a common signalling adaptor MAVS (mitochondrial antiviral‐signalling protein) leading to activation of transcription factors promoting the expression of interferons and pro‐inflammatory cytokines which reduces initial viral replication and spread
  • RLRs are tightly regulated by various proteins and post‐translational modifications to prevent undesired auto‐activation

Keywords: interferon; innate immunity; RNA viruses; pattern recognition receptor

Figure 1. Viral RNA is recognised by RIG‐I‐like receptors (RLRs), RIG‐I, MDA5 and LGP2. (a) Domain architecture of three RIG‐I‐like receptor family members RIG‐I, MDA5 and LGP2 as well as the central signalling adaptor protein, MAVS. (b) In its inactive state, both RIG‐I and MDA5 are phosphorylated at certain residues to prevent autoactivation. Phosphatases PP1α and PP1γ are two phosphatases that remove the phosphate group from RLRs bound to RNA (Weis et al., 2013). Both RLRs are then polyubiquitinated and interact with MAVS via CARD–CARD interactions (Maelfait and Beyaert, ). Activated MAVS then interacts with TRAF3, TRAF6, TRADD, RIP1, FADD and other signalling molecules (Yoneyama and Fujita, ). TRAF3 activates TBK1 and IKKϵ which phosphorylates IRF3 and IRF7 to induce type 1 interferon response (Hacker et al., ). On the other hand, MAVS interaction with RIP, FADD, TRAF6 and TRADD activates IκB kinase and activates NF‐κB. NF‐κB transcription factor drives the expression of type 1 interferon and proinflammatory cytokines (Maelfait and Beyaert, ).
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References

Anchisi S, Guerra J and Garcin D (2015) RIG‐I ATPase activity and discrimination of self‐RNA versus non‐self‐RNA. mBio 6 (2): 1–12.

Berke IC and Modis Y (2012) MDA5 cooperatively forms dimers and ATP‐sensitive filaments upon binding double‐stranded RNA. The EMBO Journal 31: 1714–1726.

Brubaker SW, Gauthier AE, Mills EW, et al. (2014) A bicistronic MAVS transcript highlights a class of truncated variants in antiviral immunity. Cell 156: 800–811.

Bruns AM, Leser GP, Lamb RA and Horvath CM (2014) The innate immune sensor LGP2 activates antiviral signaling by regulating MDA5‐RNA interaction and filament assembly. Molecular Cell 55: 771–781.

Crampton SP, Deane JA, Feigenbaum L and Bolland S (2012) Ifih1 gene dose effect reveals MDA5‐mediated chronic type I IFN gene signature, viral resistance, and accelerated autoimmunity. Journal of Immunology 188: 1451–1459.

Davis ME, Wang MK, Rennick LJ, et al. (2014) Antagonism of the phosphatase PP1 by the measles virus V protein is required for innate immune escape of MDA5. Cell Host & Microbe 16: 19–30.

Diao F, Li S, Tian Y, et al. (2007) Negative regulation of MDA5‐ but not RIG‐I‐mediated innate antiviral signaling by the dihydroxyacetone kinase. Proceedings of the National Academy of Sciences of the United States of America 104: 11706–11711.

Enevold C, Oturai AB, Sørensen PS, et al. (2009) Multiple sclerosis and polymorphisms of innate pattern recognition receptors TLR1‐10, NOD1‐2, DDX58, and IFIH1. Journal of Neuroimmunology 212: 125–131.

Funabiki M, Kato H, Miyachi Y, et al. (2014) Autoimmune disorders associated with gain of function of the intracellular sensor MDA5. Immunity 40: 199–212.

Gack MU, Kirchhofer A, Shin YC, et al. (2008) Roles of RIG‐I N‐terminal tandem CARD and splice variant in TRIM25‐mediated antiviral signal transduction. Proceedings of the National Academy of Sciences of the United States of America 105: 16743–16748.

Gao D, Yang YK, Wang RP, et al. (2009) REUL is a novel E3 ubiquitin ligase and stimulator of retinoic‐acid‐inducible gene‐I. PLoS One 4: e5760.

Hacker H, Redecke V, Blagoev B, et al. (2006) Specificity in toll‐like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature 439: 204–207.

Hayakawa S, Shiratori S, Yamato H, et al. (2011) ZAPS is a potent stimulator of signaling mediated by the RNA helicase RIG‐I during antiviral responses. Nature Immunology 12: 37–44.

Imaizumi T, Tanaka H, Tajima A, et al. (2010) Retinoic acid‐inducible gene‐I (RIG‐I) is induced by IFN‐{gamma} in human mesangial cells in culture: possible involvement of RIG‐I in the inflammation in lupus nephritis. Lupus 19: 830–836.

Jang M‐A, Kim Eun K, Now H, et al. (2015) Mutations in DDX58, which encodes RIG‐I, cause atypical Singleton‐Merten syndrome. The American Journal of Human Genetics 96: 266–274.

Jiang F, Ramanathan A, Miller MT, et al. (2011) Structural basis of RNA recognition and activation by innate immune receptor RIG‐I. Nature 479: 423–427.

Jiang X, Kinch LN, Brautigam Chad A, et al. (2012) Ubiquitin‐induced oligomerization of the RNA sensors RIG‐I and MDA5 activates antiviral innate immune response. Immunity 36: 959–973.

Kato H, Takeuchi O, Sato S, et al. (2006) Differential roles of MDA5 and RIG‐I helicases in the recognition of RNA viruses. Nature 441: 101–105.

Kohlway A, Luo D, Rawling DC, et al. (2013) Defining the functional determinants for RNA surveillance by RIG‐I. EMBO Reports 14: 772–779.

Kok KH, Lui PY, Ng MH, et al. (2011) The double‐stranded RNA‐binding protein PACT functions as a cellular activator of RIG‐I to facilitate innate antiviral response. Cell Host & Microbe 9: 299–309.

Komuro A and Horvath CM (2006) RNA‐ and virus‐independent inhibition of antiviral signaling by RNA helicase LGP2. Journal of Virology 80: 12332–12342.

Kowalinski E, Lunardi T, McCarthy AA, et al. (2011) Structural basis for the activation of innate immune pattern‐recognition receptor RIG‐I by viral RNA. Cell 147: 423–435.

Li X, Ranjith‐Kumar CT, Brooks MT, et al. (2009) The RIG‐I‐like receptor LGP2 recognizes the termini of double‐stranded RNA. The Journal of Biological Chemistry 284: 13881–13891.

Lu C, Xu H, Ranjith‐Kumar CT, et al. (2010) The structural basis of 5' triphosphate double‐stranded RNA recognition by RIG‐I C‐terminal domain. Structure 18: 1032–1043.

Luo D, Ding SC, Vela A, et al. (2011) Structural insights into RNA recognition by RIG‐I. Cell 147: 409–422.

Luo D, Kohlway A and Pyle AM (2013) Duplex RNA activated ATPases (DRAs): platforms for RNA sensing, signaling and processing. RNA Biology 10: 111–120.

Luo D, Kohlway A, Vela A and Pyle AM (2012) Visualizing the determinants of viral RNA recognition by innate immune sensor RIG‐I. Structure 20: 1983–1988.

Maelfait J and Beyaert R (2012) Emerging role of ubiquitination in antiviral RIG‐I signaling. Microbiology and Molecular Biology Reviews 76: 33–45.

Martinez A, Varade J, Lamas JR, et al. (2008) Association of the IFIH1‐GCA‐KCNH7 chromosomal region with rheumatoid arthritis. Annals of the Rheumatic Diseases 67: 137–138.

Mesman AW, Zijlstra‐Willems EM, Kaptein TM, et al. (2014) Measles virus suppresses RIG‐I‐like receptor activation in dendritic cells via DC‐SIGN‐mediated inhibition of PP1 phosphatases. Cell Host & Microbe 16: 31–42.

Nakashima R, Imura Y, Kobayashi S, et al. (2010) The RIG‐I‐like receptor IFIH1/MDA5 is a dermatomyositis‐specific autoantigen identified by the anti‐CADM‐140 antibody. Rheumatology 49: 433–440.

Narita R, Takahasi K, Murakami E, et al. (2014) A novel function of human pumilio proteins in cytoplasmic sensing of viral infection. PLoS Pathogens 10: e1004417.

Nejentsev S, Walker N, Riches D, et al. (2009) Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324: 387–389.

Oshiumi H, Miyashita M, Inoue N, et al. (2010) The ubiquitin ligase riplet is essential for RIG‐I‐dependent innate immune responses to RNA virus infection. Cell Host & Microbe 8: 496–509.

Peisley A, Wu B, Yao H, et al. (2013) RIG‐I forms signaling‐competent filaments in an ATP‐dependent, ubiquitin‐independent manner. Molecular Cell 51: 573–583.

Potter J, Randall R and Taylor G (2008) Crystal structure of human IPS‐1/MAVS/VISA/Cardif caspase activation recruitment domain. BMC Structural Biology 8: 11.

Rice GI, del Toro DY, Jenkinson EM, et al. (2014) Gain‐of‐function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nature Genetics 46: 503–509.

Rodriguez KR, Bruns AM and Horvath CM (2014) MDA5 and LGP2: accomplices and antagonists of antiviral signal transduction. Journal of Virology 88: 8194–8200.

Rothenfusser S, Goutagny N, DiPerna G, et al. (2005) The RNA helicase Lgp2 inhibits TLR‐independent sensing of viral replication by retinoic acid‐inducible gene‐I. The Journal of Immunology 175: 5260–5268.

Saito T, Hirai R, Loo Y‐M, et al. (2007) Regulation of innate antiviral defenses through a shared repressor domain in RIG‐I and LGP2. Proceedings of the National Academy of Sciences of the United States of America 104: 582–587.

Satoh T, Kato H, Kumagai Y, et al. (2010) LGP2 is a positive regulator of RIG‐I‐ and MDA5‐mediated antiviral responses. Proceedings of the National Academy of Sciences 107: 1512–1517.

Schlee M (2013) Master sensors of pathogenic RNA – RIG‐I like receptors. Immunobiology 218: 1322–1335.

Suarez‐Calvet X, Gallardo E, Nogales‐Gadea G, et al. (2014) Altered RIG‐I/DDX58‐mediated innate immunity in dermatomyositis. The Journal of Pathology 233: 258–268.

Wang Y, Ludwig J, Schuberth C, et al. (2010) Structural and functional insights into 5'‐ppp RNA pattern recognition by the innate immune receptor RIG‐I. Nature Structural & Molecular Biology 17: 781–787.

Wies E, Wang MK, Maharaj NP, et al. (2013) Dephosphorylation of the RNA sensors RIG‐I and MDA5 by the phosphatase PP1 is essential for innate immune signaling. Immunity 38: 437–449.

Wu B, Peisley A, Richards C, et al. (2013) Structural basis for dsRNA recognition, filament formation, and antiviral signal activation by MDA5. Cell 152: 276–289.

Yao H, Dittmann M, Peisley A, et al. (2015) ATP‐dependent effector‐like functions of RIG‐I‐like receptors. Molecular Cell 58: 541–548.

Yoneyama M, Kikuchi M, Matsumoto K, et al. (2005) Shared and unique functions of the DExD/H‐box helicases RIG‐I, MDA5, and LGP2 in antiviral innate immunity. The Journal of Immunology 175: 2851–2858.

Yoneyama M and Fujita T (2009) RNA recognition and signal transduction by RIG‐I‐like receptors. Immunological Review 227: 54–65.

Zheng J, Yong HY, Panutdaporn N, et al. (2015) High‐resolution HDX‐MS reveals distinct mechanisms of RNA recognition and activation by RIG‐I and MDA5. Nucleic Acids Research 43: 1216–1230.

Further Reading

Eisenacher K and Krug A (2012) Regulation of RLR‐mediated innate immune signaling – it is all about keeping the balance. European Journal of Cell Biology 91: 36–47.

Chiang JJ, Davis ME and Gack MU (2014) Regulation of RIG‐I‐like receptor signaling by host and viral proteins. Cytokine & Growth Factor Reviews 25: 491–505.

Hiscott J, Lin R, Nakhaei P and Paz S (2006) MasterCARD: a priceless link to innate immunity. Trends in Molecular Medicine 12: 53–56.

Kato H, Takahasi K and Fujita T (2011) RIG‐I‐like receptors: cytoplasmic sensors for non‐self RNA. Immunological Reviews 243: 91–98.

Loo YM and Gale M Jr (2011) Immune signaling by RIG‐I‐like receptors. Immunity 34: 680–692.

Nakhaei P, Genin P, Civas A and Hiscott J (2009) RIG‐I‐like receptors: sensing and responding to RNA virus infection. Seminars in Immunology 21: 215–222.

Related Sub-Topics:

RNA Viruses | Autoimmunity | Innate Immunity | Intracellular and Extracellular Signalling | Infection
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Article Title: RIG‐I‐Like Receptors
 
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Yong, Hui Yee, and Luo, Dahai(Nov 2015) RIG‐I‐Like Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026237]