RIG-I-like receptor regulation in virus infection and immunity

Abstract

Mammalian cells have the intrinsic capacity to detect viral pathogens and to initiate an antiviral response that is characterized by the induction of interferons (IFNs) and proinflammatory cytokines. A delicate regulation of the signaling pathways that lead to cytokine production is needed to ensure effective clearance of the virus, while preventing tissue damage caused by excessive cytokine release. Here, we focus on the mechanisms that modulate the signal transduction triggered by RIG-I-like receptors (RLRs) and their adaptor protein MAVS, key components of the host machinery for sensing foreign RNA. Specifically, we summarize recent advances in understanding how RLR signaling is regulated by posttranslational and posttranscriptional mechanisms, microRNAs (miRNAs) and autophagy. We further discuss how viruses target these regulatory mechanisms for immune evasion.

Figure 1

Regulation of RLR signaling, as exemplified by RIG-I. RIG-I is kept in an inactive phosphorylated state in resting cells by PKCα/β and CKII. Upon engagement of viral RNA, RIG-I undergoes a conformational change and is dephosphorylated by PP1α/γ. Subsequently, activation of RIG-I is mediated by K63-linked ubiquitination of the CTD and CARD domains by Riplet and TRIM25, respectively, promoting RIG-I tetramerization. OASL can mimic K63-linked ubiquitination to promote RIG-I activation. The adaptor protein 14-3-3ɛ mediates translocation of the active RIG-I-TRIM25 complex to mitochondrion/MAM-localized MAVS, leading to downstream signal transduction that results in type I IFN gene expression (not illustrated). The deubiquitinating enzymes CYLD, USP21 and USP3 remove K63-linked polyubiquitin chains from RIG-I as a form of homeostatic regulation to prevent aberrant IFN induction. The expression of CYLD is suppressed by miR-526a. TRIM25, RIG-I and MAVS are further regulated by degradative K48-linked ubiquitination mediated by LUBAC, RNF125, and AIP4, Smurf1, and RNF5, respectively. Conversely, USP15 and USP4 deubiquitinate TRIM25 and RIG-I, respectively, to stabilize the proteins. The Atg5–Atg12 conjugate and Sec14L1 block RIG-I–MAVS interaction to prevent antiviral signaling. A RIG-I splice variant (RIG-I SV), MAVS splice variant (MAVS1a) and miniMAVS also contribute to prevent excessive signaling.

Figure 2

Pathogenic viruses target RLR regulation for immune evasion. There are five general strategies used by viruses to target RLR–MAVS signaling: (1) modulation of PTMs of RLRs, (2) cleavage of RLR pathway components, (3) sequestration of RLRs, (4) modulation of RLR localization, and (5) degradation of MAVS and other RLR downstream signaling molecules. The details of the viral antagonistic mechanisms are described in the text.