RIG-I like receptors in antiviral immunity and therapeutic applications

Abstract

The RNA helicase family of RIG-I-like receptors (RLRs) is a key component of host defense mechanisms responsible for detecting viruses and triggering innate immune signaling cascades to control viral replication and dissemination. As cytoplasm-based sensors, RLRs recognize foreign RNA in the cell and activate a cascade of antiviral responses including the induction of type I interferons, inflammasome activation, and expression of proinflammatory cytokines and chemokines. This review provides a brief overview of RLR function, ligand interactions, and downstream signaling events with an expanded discussion on the therapeutic potential of targeting RLRs for immune stimulation and treatment of virus infection.

Keywords: RIG-I; adjuvant; inflammation.

Figure 1.

Potential models of RIG-I-like receptors (RLRs) surveillance and activation. (A) Activation model. RIG-I is held in a signaling-off conformation through intramolecular interactions between the repressor and CARD domains. During virus infection, RIG-I repressor domain binding to high-affinity RNA ligand PAMP motifs (red box) leads to RIGI activation and the release of the CARD domains for interaction with IPS-1 localized on intracellular membranes, ultimately activating signaling proteins within an IPS-1 “signalosome” that drives the innate immune antiviral response. (B) Amplification model. During virus infection, OAS is activated, producing 2–5 A, which in turn, activates RNAse-L cleavage of self and/or viral RNA substrates (delineated in blue), and generating products that then serve as RIG-I and MDA5 ligands. Binding of RIG-I or MDA5 to the RNAse-L-generated RNA products occurs later during virus infection and is supported by increased RLR levels produced as a result of IFN signaling, thus creating an amplification of RLR signaling. (C) Surveillance model. Powered by ATP hydrolysis, a single RIG-I molecule or molecular unit repeatedly moves across an RNA molecule, but without dissociating. Once the RIG-I molecule encounters a PAMP motif, it stalls on the RNA, and ATP hydrolysis drives a conformation change to trigger RIG-I signaling activation, thus allowing it to bind to IPS-1 and induce the innate immune response.