Role of RIG1-like Receptors in Antiviral Innate Immunity

The antiviral innate immunity response follows viral infection and the detection of viral components by the host pattern recognition receptors (PRRs), consisting of two main families: Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs). The Toll-like receptors are located at the cell surface and recognize extracellular viruses, whereas the RIG-I-like receptors are present in the cytoplasm and recognize 5'-phosphate-containing viral RNA. The family of RIG-I-like receptors is composed of three members: retinoic acid inducible gene-I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2). While MDA5 is essential for the recognition of dsRNA of Picornaviruses, RIG-I is involved in the recognition of uncapped 5'-phosphate dsRNA or ssRNA found in Flaviviruses, Orthomyxoviruses, Paramyxoviruses, Rhabdoviruses and the Japanese encephalitis virus. RIG-I is also implicated in the sensing of Epstein-Barr virus non-translated EBER RNAs.Following ligand recognition, RIG-I and MDA5 initiate an intracellular signaling cascade leading to the production of type-1 interferon and proinflammatory cytokines, which trigger the antiviral innate immune response. Upon ligand binding, RIG-I and MDA5 both interact with the adaptor protein IPS-1, which in turn signal through TRAF3, TANK, TBK1, and IKKε leading to the activation and dimerization of phosphorylated IRF-3 and IRF-7. These two transcription factors translocate to the nucleus and induce the transcription of type-1 interferons. IPS-1 can also interact with TRAF2, TRAF6, FADD, and RIPK1, leading to the activation of the NF-κB pathway and subsequent transcription of IFN-β. Although LPG2 is able to bind dsRNA, it lacks a downstream signal domain and therefore does not signal itself. However, LPG2 has an inhibitory function in RIG-I/MDA5-mediated signaling. Viruses have adapted strategies to interfere with the host immune response. Various proteins encoded by RNA viruses are able to antagonize the RIG-I-like receptors signaling pathway.