RIG‐I‐Like Receptors


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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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.

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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.

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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]