Immune signaling by RIG-I-like receptors

Abstract

The RIG-I-like receptors (RLRs) RIG-I, MDA5, and LGP2 play a major role in pathogen sensing of RNA virus infection to initiate and modulate antiviral immunity. The RLRs detect viral RNA ligands or processed self RNA in the cytoplasm to trigger innate immunity and inflammation and to impart gene expression that serves to control infection. Importantly, RLRs cooperate in signaling crosstalk networks with Toll-like receptors and other factors to impart innate immunity and to modulate the adaptive immune response. RLR regulation occurs at a variety of levels ranging from autoregulation to ligand and cofactor interactions and posttranslational modifications. Abberant RLR signaling or dysregulation of RLR expression is now implicated in the development of autoimmune diseases. Understanding the processes of RLR signaling and response will provide insights to guide RLR-targeted therapeutics for antiviral and immune-modifying applications.

Figure 1. Structural representation of the RLRs and their adaptor IPS-1

Key structural domains involved in signaling are shown. The RLRs consists 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.

Figure 2. Model for RIG-I signaling activation and its regulation

In the resting state, RIG-I is held in a “closed” conformation in the resting state 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 and other nonself signature(s), concommitant with K63-linked ubiquitination of RIG-I by TRIM25 and RING finger protein leading to RIG-I activation (Ripletotherwise 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/UCmotif such as the HCV RNA genome (Saito, Owen 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 singalosome. 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.