Regulation of antiviral innate immune signaling by stress-induced RNA granules

Abstract

Activation of antiviral innate immunity is triggered by cellular pattern recognition receptors. Retinoic acid inducible gene-I (RIG-I)-like receptors (RLRs) detect viral non-self RNA in cytoplasm of virus-infected cells and play a critical role in the clearance of the invaded viruses through production of antiviral cytokines. Among the three known RLRs, RIG-I and melanoma differentiation-associated gene 5 recognize distinct non-self signatures of viral RNA and activate antiviral signaling. Recent reports have clearly described the molecular machinery underlying the activation of RLRs and interactions with the downstream adaptor, mitochondrial antiviral signaling protein (MAVS). RLRs and MAVS are thought to form large multimeric filaments around cytoplasmic organelles depending on the presence of Lys63-linked ubiquitin chains. Furthermore, RLRs have been shown to localize to stress-induced ribonucleoprotein aggregate known as stress granules and utilize them as a platform for recognition/activation of signaling. In this review, we will focus on the current understanding of RLR-mediated signal activation and the interactions with stress-induced RNA granules.

Keywords: RNA; innate immunity; retinoic acid inducible gene-I-like receptor; stress response; viral infection.

Fig. 1

Structure of RLRs and MAVS. The three RLRs contain a CTD, DExD/H box-containing RNA helicase domain (Hel-1, Hel-2i and Hel-2) and pincer domain. RIG-I and MDA5 have N-terminal tandem CARDs (2CARD). MAVS has a single CARD at its N-terminal region, three TRAF-binding motifs (TBMs) and a C-terminal transmembrane domain (TM). Modified from Yoneyama et al. (2015), Viral RNA detection by RIG-I-like receptors, Curr Opin Immunol, 32, 48–53, Copyright (2015), with permission from Elsevier (81).

Fig. 2

Molecular mechanisms of RLR activation. RIG-I and MDA5 are localized in the cytoplasm in an inactive configuration. In response to viral infection, RIG-I and MDA5 recognize viral non-self RNAs, i.e. 5′-ppp-containing panhandle dsRNA and long dsRNA, respectively, and induce ATP-dependent conformational changes to form filamentous oligomers on the substrates. The C-terminal half of RIG-I preferentially recognizes the 5′-ppp structure using the basic cleft of CTD, whereas MDA5 does not have an end-preference. The released N-terminal 2CARDs form a ‘lock-washer’-like tetramer in a Lys63-linked Ubs-dependent manner. The CARD of MAVS on the mitochondria forms a filament along the 2CARD tetramer, resulting in recruitment of downstream signaling molecules, such as TRAFs and IKKs, which activate the transcription factors, IRF-3/7 and NF-κB. Modified from Yoneyama et al. (2015), Viral RNA detection by RIG-I-like receptors, Curr Opin Immunol, 32, 48–53, Copyright (2015), with permission from Elsevier (81).

Fig. 3

Interaction between RLR-mediated signaling and RNA granules. In response to viral infection, viral dsRNAs can activate not only RLRs but also PKR. PKR phosphorylates eIF2α at Ser51 residue and terminates initiation of cellular translation, resulting in inhibition of viral replication. The translation-stalled cellular mRNAs and RBPs transiently accumulate in SGs. Although SGs are known to communicate with PBs, the precise mechanisms remain unclear. In virus-induced SGs, viral dsRNA and viral proteins are localized with RLRs and other antiviral proteins, suggesting that SGs may function as a platform for antiviral signaling. Some viruses have viral proteins that positively inhibit the formation of SGs to escape from antivirus activities, whereas some exploit SGs for their efficient growth.