Immune Signaling by RIG-I-like Receptors

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Immune Signaling by RIG-I-like Receptors Yueh-Ming Loo, Michael Gale  Immunity  Volume 34, Issue 5, Pages 680-692 (May 2011) DOI: 10.1016/j.immuni.2011.05.003 Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 1 Structural Representation of the RLRs and Their Adaptor IPS-1 Key structural domains involved in signaling are shown. The RLRs consist of CARD (caspase activation and recruitment domain); ATPase containing DEAD box helicase (DEAD helicase); and a C-terminal domain (CTD) that in RIG-I and LGP2 but not MDA5 encodes a repressor domain (RD) involved in autoregulation. LGP2 lacks the N-terminal CARDs. IPS-1 consists of a homologous CARD, a proline-rich region (Pro), and a transmembrane domain (TM) on its C terminus. Immunity 2011 34, 680-692DOI: (10.1016/j.immuni.2011.05.003) Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 2 Model for RIG-I Signaling Activation and Its Regulation In the resting state, RIG-I is held in a “closed” conformation by casein kinase II phosphorylation and autoregulatory intramolecular interactions with the C-terminal RD within the CTD holds the CARDs unavailable for signaling. During virus infection, RD engagement of a 5′ppp RNA PAMP containing other nonself signature(s), concommitant with K63-linked ubiquitination of RIG-I by TRIM25 and RING finger protein leading to RIG-I activation (Riplet, otherwise known as REUL or RNF135), leads to conformational changes that release the CARDs from autoregulation. The model shows RIG-I binding to 5′ppp RNA containing poly-U/UC motif such as the HCV RNA genome (Saito et al., 2008; Uzri and Gehrke, 2009). RIG-I then assumes an “open” conformation that allows for oligomerization and CARD-dependent interaction with IPS-1, which activates signaling molecules at the IPS-1 signalosome. These interactions trigger a signaling cascade that culminates in IFN production and expression of proteins with direct antiviral or immune-modulating activities to control infection. To prevent excessive activation of innate immune responses, RIG-I signaling activity is inhibited by (1) phosphorylation events that inhibit the K63-linked ubiquitination required for signaling activation, (2) negative regulators that sequester PAMP from RIG-I, (3) association with negative regulators or molecules that disrupt/destabilize its interaction with IPS-1, and (4) K43-linked ubiquitination by RNF125, which targets RIG-I for proteasomal degradation. Immunity 2011 34, 680-692DOI: (10.1016/j.immuni.2011.05.003) Copyright © 2011 Elsevier Inc. Terms and Conditions