Abstract
Type I interferon (IFN) induces many antiviral factors in host cells. RIG-I-like receptors (RLRs) are cytoplasmic viral RNA sensors that trigger the signal to induce the innate immune response that includes type I IFN production. RIG-I and MDA5 are RLRs that form nucleoprotein filaments along viral double-stranded RNA, resulting in the activation of MAVS adaptor molecule. The MAVS protein forms a prion-like aggregation structure, leading to type I IFN production. RIG-I and MDA5 undergo post-translational modification. TRIM25 and Riplet ubiquitin ligases deliver a K63-linked polyubiquitin moiety to the RIG-I N-terminal caspase activation and recruitment domains (CARDs) and C-terminal region; the polyubiquitin chain then stabilizes the two-CARD tetramer structure required for MAVS assembly. MDA5 activation is regulated by phosphorylation. RIOK3 is a protein kinase that phosphorylates the MDA5 protein in a steady state, and PP1α/γ dephosphorylate this protein, resulting in its activation. RIG-I and MDA5 require cytoplasmic RNA helicases for their efficient activation. LGP2, another RLR, is an RNA helicase involved in RLR signaling. This protein does not possess N-terminal CARDs and, thus, cannot trigger downstream signaling by itself. Recent studies have revealed that this protein modulates MDA5 filament formation, resulting in enhanced type I IFN production. Several other cytoplasmic RNA helicases are involved in RLR signaling. DDX3, DHX29, DHX36, and DDX60 RNA helicases have been reported to be involved in RLR-mediated type I IFN production after viral infection. However, the underlying mechanism is largely unknown. Future studies are required to reveal the role of RNA helicases in the RLR signaling pathway.
Highlights
The innate immune system is the first line of defense against viral infection
Gack and colleagues first reported the K63-linked polyubiquitination of RIG-I caspase activation and recruitment domains (CARDs) by TRIM25 ubiquitin ligase, which is essential for their activation [16]
The knockout (KO) of each ubiquitin ligase has been shown to markedly reduce RIG-I-mediated type I IFN production [16, 20]. These ubiquitin ligases are targeted by several viral proteins, such as NS-1 of influenza A virus and NS3-4A of hepatitis C virus (HCV), resulting in the attenuation of RIG-I-mediated type I IFN production [19, 21]
Summary
The innate immune system is the first line of defense against viral infection. RIG-I-like receptors (RLRs) are cytoplasmic viral RNA sensors that recognizes viral double-stranded (ds) RNA and trigger antiviral innate immune responses [1]. The RIG-I and MDA5 proteins, which are members of RLRs, comprise two caspase activation and recruitment domains (CARDs), a helicase domain, and a C-terminal domain (CTD) [2]. The helicase domain and CTD bind to viral RNA, and CTD is essential for the recognition of viral RNA [3, 4]. After the recognition of viral RNA, two N-terminal
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