Cytoplasmic Sensing of Viral Double-Stranded RNA and Activation of Innate Immunity by RIG-I-Like Receptors

  • Mitsutoshi Yoneyama
  • Takashi Fujita


Innate antiviral reactions are induced within hours of a viral infection. These reactions are critical to the activation of adaptive immunity. The major innate antiviral reaction is that mediated by type I and III interferons (IFNs), which activate antiviral genes through cell surface receptors, signal transducers, and transcription factors (Samuel. Clin Microbiol Rev 14:778–809, 2001; Theofilopoulos et al. Annu Rev Immunol 23:307–336, 2005; Uze and Monneron. Biochimie 89:729–734, 2007). Once the antiviral gene products establish an antiviral state, viral replication is selectively repressed. Efficient expression of IFN is observed in cells infected with viruses, suggesting that viral components produced during replication are detected by cellular sensors. A family of RNA helicases termed RIG-I-like receptors (RLRs), including retinoic acid-inducible gene-I (RIG-I), melanoma differentiation associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2), senses viral double-stranded (ds) RNA and triggers an antiviral program including the production of IFN (Kawai and Akira. Ann N Y Acad Sci 1143:1–20, 2008; Yoneyama and Fujita. Immunol Rev 227:54–65, 2009). We review here the structure and function of RLRs.


West Nile Virus Newcastle Disease Virus Japanese Encephalitis Virus Repression Domain Antiviral Signaling 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Ablasser A, Bauernfeind F, Hartmann G et al (2009) RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate. Nat Immunol 10(10):1065–1072PubMedCrossRefGoogle Scholar
  2. Arimoto K, Takahashi H, Hishiki T et al (2007) Negative regulation of the RIG-I signaling by the ubiquitin ligase RNF125. Proc Natl Acad Sci U S A 104:7500–7505PubMedCrossRefGoogle Scholar
  3. Balachandran S, Thomas E, Barber GN (2004) A FADD-dependent innate immune mechanism in mammalian cells. Nature 432:401–405PubMedCrossRefGoogle Scholar
  4. Besch R, Poeck H, Hohenauer T et al (2009) Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon-independent apoptosis in human melanoma cells. J Clin Invest 119:2399–2411PubMedGoogle Scholar
  5. Chiu YH, Macmillan JB, Chen ZJ (2009) RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell 138:576–591PubMedCrossRefGoogle Scholar
  6. Cui S, Eisenacher K, Kirchhofer A et al (2008) The C-terminal regulatory domain is the RNA 5’-triphosphate sensor of RIG-I. Mol Cell 29:169–179PubMedCrossRefGoogle Scholar
  7. 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. Proc Natl Acad Sci USA 104:11706–11711PubMedCrossRefGoogle Scholar
  8. Fredericksen BL, Keller BC, Fornek J et al (2008) Establishment and maintenance of the innate antiviral response to West Nile Virus involves both RIG-I and MDA5 signaling through IPS-1. J Virol 82:609–616PubMedCrossRefGoogle Scholar
  9. Friedman CS, O’Donnell MA, Legarda-Addison D et al (2008) The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response. EMBO Rep 9:930–936PubMedCrossRefGoogle Scholar
  10. Gack MU, Shin YC, Joo CH et al (2007) TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 446:916–920PubMedCrossRefGoogle Scholar
  11. 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:e5760PubMedCrossRefGoogle Scholar
  12. Hornung V, Ellegast J, Kim S et al (2006) 5’-Triphosphate RNA is the ligand for RIG-I. Science 314:994–997PubMedCrossRefGoogle Scholar
  13. Ishikawa H, Barber GN (2008) STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455:674–678PubMedCrossRefGoogle Scholar
  14. Jounai N, Takeshita F, Kobiyama K et al (2007) The Atg5 Atg12 conjugate associates with innate antiviral immune responses. Proc Natl Acad Sci USA 104:14050–14055PubMedCrossRefGoogle Scholar
  15. Kato H, Sato S, Yoneyama M et al (2005) Cell type-specific involvement of RIG-I in antiviral response. Immunity 23:19–28PubMedCrossRefGoogle Scholar
  16. Kato H, Takeuchi O, Sato S et al (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–105PubMedCrossRefGoogle Scholar
  17. Kato H, Takeuchi O, Mikamo-Satoh E et al (2008) Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J Exp Med 205:1601–1610PubMedCrossRefGoogle Scholar
  18. Kawai T, Akira S (2008) Toll-like receptor and RIG-I-like receptor signaling. Ann N Y Acad Sci 1143:1–20PubMedCrossRefGoogle Scholar
  19. Kawai T, Takahashi K, Sato S et al (2005) IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol 6:981–988PubMedCrossRefGoogle Scholar
  20. Kayagaki N, Phung Q, Chan S et al (2007) DUBA: A deubiquitinase that regulates type I interferon production. Science 318:1628–1632PubMedCrossRefGoogle Scholar
  21. Komuro A, Horvath CM (2006) RNA- and virus-independent inhibition of antiviral signaling by RNA helicase LGP2. J Virol 80:12332–12342PubMedCrossRefGoogle Scholar
  22. Li X, Lu C, Stewart M et al (2009) Structural basis of double-stranded RNA recognition by the RIG-I like receptor MDA5. Arch Biochem Biophys 488:23–33PubMedCrossRefGoogle Scholar
  23. Lin R, Lacoste J, Nakhaei P et al (2006a) Dissociation of a MAVS/IPS-1/VISA/Cardif-IKKepsilon molecular complex from the mitochondrial outer membrane by hepatitis C virus NS3-4A ­proteolytic cleavage. J Virol 80:6072–6083PubMedCrossRefGoogle Scholar
  24. Lin R, Yang L, Nakhaei P et al (2006b) Negative regulation of the retinoic acid-inducible gene I-induced antiviral state by the ubiquitin-editing protein A20. J Biol Chem 281:2095–2103PubMedCrossRefGoogle Scholar
  25. Loo YM, Owen DM, Li K et al (2006) Viral and therapeutic control of IFN-beta promoter stimulator 1 during hepatitis C virus infection. Proc Natl Acad Sci USA 103:6001–6006PubMedCrossRefGoogle Scholar
  26. Loo YM, Fornek J, Crochet N et al (2008) Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J Virol 82:335–345PubMedCrossRefGoogle Scholar
  27. Meylan E, Curran J, Hofmann K et al (2005) Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437:1167–1172PubMedCrossRefGoogle Scholar
  28. Michallet MC, Meylan E, Ermolaeva MA et al (2008) TRADD protein is an essential component of the RIG-like helicase antiviral pathway. Immunity 28:651–661PubMedCrossRefGoogle Scholar
  29. Moore CB, Bergstralh DT, Duncan JA et al (2008) NLRX1 is a regulator of mitochondrial antiviral immunity. Nature 451:573–577PubMedCrossRefGoogle Scholar
  30. Oganesyan G, Saha SK, Guo B et al (2006) Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature 439:208–211PubMedCrossRefGoogle Scholar
  31. Oshiumi H, Matsumoto M, Hatakeyama S et al (2009) Riplet/RNF135, a RING finger protein, ubiquitinates RIG-I to promote interferon-beta induction during the early phase of viral infection. J Biol Chem 284:807–817PubMedCrossRefGoogle Scholar
  32. Pichlmair A, Schulz O, Tan CP et al (2006) RIG-I-mediated antiviral responses to single-stranded RNA bearing 5’-phosphates. Science 314:997–1001PubMedCrossRefGoogle Scholar
  33. Pippig DA, Hellmuth JC, Cui S et al (2009) The regulatory domain of the RIG-I family ATPase LGP2 senses double-stranded RNA. Nucleic Acids Res 37:2014–2025PubMedCrossRefGoogle Scholar
  34. 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. J Immunol 175:5260–5268PubMedGoogle Scholar
  35. Saha SK, Pietras EM, He JQ et al (2006) Regulation of antiviral responses by a direct and specific interaction between TRAF3 and Cardif. EMBO J 25:3257–3263PubMedCrossRefGoogle Scholar
  36. Saito T, Hirai R, Loo YM et al (2007) Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2. Proc Natl Acad Sci USA 104:582–587PubMedCrossRefGoogle Scholar
  37. Samuel CE (2001) Antiviral actions of interferons. Clin Microbiol Rev 14:778–809PubMedCrossRefGoogle Scholar
  38. Schlee M, Roth A, Hornung V et al (2009) Recognition of 5’ triphosphate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus. Immunity 31:25–34PubMedCrossRefGoogle Scholar
  39. Schmidt A, Schwerd T, Hamm W et al (2009) 5’-triphosphate RNA requires base-paired structures to activate antiviral signaling via RIG-I. Proc Natl Acad Sci USA 106:12067–12072PubMedCrossRefGoogle Scholar
  40. Seth RB, Sun L, Ea CK et al (2005) Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122:669–682PubMedCrossRefGoogle Scholar
  41. Sumpter R Jr, Loo YM, Foy E et al (2005) Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I. J Virol 79:2689–2699PubMedCrossRefGoogle Scholar
  42. Tabara H, Yigit E, Siomi H et al (2002) The dsRNA binding protein RDE-4 interacts with RDE-1, DCR-1, and a DExH-box helicase to direct RNAi in C. elegans. Cell 109:861–871PubMedCrossRefGoogle Scholar
  43. Takahasi K, Yoneyama M, Nishihori T et al (2008) Nonself RNA-sensing mechanism of RIG-I helicase and activation of antiviral immune responses. Mol Cell 29:428–440PubMedCrossRefGoogle Scholar
  44. Tal MC, Sasai M, Lee HK et al (2009) Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling. Proc Natl Acad Sci U S A 106:2770–2775PubMedCrossRefGoogle Scholar
  45. Theofilopoulos AN, Baccala R, Beutler B et al (2005) Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol 23:307–336PubMedCrossRefGoogle Scholar
  46. Uze G, Monneron D (2007) IL-28 and IL-29: Newcomers to the interferon family. Biochimie 89:729–734PubMedCrossRefGoogle Scholar
  47. Venkataraman T, Valdes M, Elsby R et al (2007) Loss of DExD/H box RNA helicase LGP2 manifests disparate antiviral responses. J Immunol 178:6444–6455PubMedGoogle Scholar
  48. Wang Y, Zhang HX, Sun YP et al (2007) Rig-I−/− mice develop colitis associated with downregulation of G alpha i2. Cell Res 17:858–868PubMedCrossRefGoogle Scholar
  49. Wang F, Gao X, Barrett JW et al (2008) RIG-I mediates the co-induction of tumor necrosis factor and type I interferon elicited by myxoma virus in primary human macrophages. PLoS Pathog 4:e1000099PubMedCrossRefGoogle Scholar
  50. Xu LG, Wang YY, Han KJ et al (2005) VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell 19:727–740PubMedCrossRefGoogle Scholar
  51. Yasukawa K, Oshiumi H, Takeda M et al (2009) Mitofusin 2 inhibits mitochondrial antiviral ­signaling. Sci Signal 2:ra47PubMedCrossRefGoogle Scholar
  52. Yoneyama M, Fujita T (2009) RNA recognition and signal transduction by RIG-I-like receptors. Immunol Rev 227:54–65PubMedCrossRefGoogle Scholar
  53. Yoneyama M, Kikuchi M, Natsukawa T et al (2004) The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 5:730–737PubMedCrossRefGoogle Scholar
  54. 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. J Immunol 175:2851–2858PubMedGoogle Scholar
  55. Yoshida R, Takaesu G, Yoshida H et al (2008) TRAF6 and MEKK1 play a pivotal role in the RIG-I-like helicase antiviral pathway. J Biol Chem 283:36211–36220PubMedCrossRefGoogle Scholar
  56. Zhang M, Wu X, Lee AJ et al (2008) Regulation of IkappaB kinase-related kinases and antiviral responses by tumor suppressor CYLD. J Biol Chem 283:18621–18626PubMedCrossRefGoogle Scholar
  57. Zhong B, Yang Y, Li S et al (2008) The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29:538–550PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Laboratory of Molecular Genetics, Institute for Virus Research, and Laboratory of Molecular Cell Biology, Graduate School of BiostudiesKyoto UniversityKyotoJapan
  2. 2.PRESTO, Japan Science and Technology AgencySaitamaJapan

Personalised recommendations