Activation of RIG-I-like receptor signal transduction

Abstract

Mammalian cells have the ability to recognize virus infection and mount a powerful antiviral response. Pattern recognition receptor proteins detect molecular signatures of virus infection and activate antiviral signaling cascades. The RIG-I-like receptors are cytoplasmic DExD/H box proteins that can specifically recognize virus-derived RNA species as a molecular feature discriminating the pathogen from the host. The RIG-I-like receptor family is composed of three homologous proteins, RIG-I, MDA5, and LGP2. All of these proteins can bind double-stranded RNA species with varying affinities via their conserved DExD/H box RNA helicase domains and C-terminal regulatory domains. The recognition of foreign RNA by the RLRs activates enzymatic functions and initiates signal transduction pathways resulting in the production of antiviral cytokines and the establishment of a broadly effective cellular antiviral state that protects neighboring cells from infection and triggers innate and adaptive immune systems. The propagation of this signal via the interferon antiviral system has been studied extensively, while the precise roles for enzymatic activities of the RNA helicase domain in antiviral responses are only beginning to be elucidated. Here, current models for RLR ligand recognition and signaling are reviewed.

Figure 1. Signal Transduction by the RIG-I-like receptors

The RIG-I-like receptors (RIG-I: blue, MDA5: orange, and LGP2: green) are activated upon recognition of virus-derived RNA (red stars/lines). RIG-I is present in the cytoplasm in an autoinhibited state, and upon activation a conformational change exposes the CARD domains for interaction with IPS-1. Activated RIG-I and MDA5 both signal through IPS-1 and their signaling activity may be positively regulated by LGP2. IPS-1 transmits the signal through protein kinase complexes leading to the activation of NFκB and IRF3 transcription factors, resulting in the production of IFN-β and other cytokines that initiate antiviral immunity. See text for details. A color version of this figure is available online.

Figure 2. Diagram of the structural protein domains of RIG-I, MDA5, and LGP2

A.) The RLRs are composed of a shared central DExD/H box helicase domain (green) containing conserved helicase motifs (roman numerals) which function to coordinate RNA binding and ATP hydrolysis. The C-terminal regulatory domain (CTD or RD, pink) implicated in RNA binding and inhibition of basal RIG-I signaling. RIG-I and MDA5 contain two tandem caspase activation and recruitment (CARD) domains (blue) that are critical for downstream signaling activity. The paramyxovirus V protein targets MDA5 and LGP2 at a minimal region coinciding with the boundaries of helicase domain 2 (motifs IV, V, and VI). B.) Tables comparing the percent amino acid identity of the full length RLR proteins and defined protein domains. A color version of this figure is available online.

Figure 3. Potential model of LGP2 function

A.) LGP2 may have enzymatic activity capable of remodeling RNA substrates, making them more readily detectable by RIG-I and MDA5, thus serving a positive role in antiviral signaling. B.) During steady state and initially during virus infection the concentrations of LGP2 may be low, allowing LGP2 to function independently or together with RIG-I and MDA5 to positively regulate signaling, perhaps by remodeling RNA substrates (see 3A). LGP2 is inducible by antiviral stimuli, and accumulation of LGP2 to higher levels would allow it to interact with other proteins (blue box, red oval) to form complexes capable of inhibiting RIG-I- and MDA5-mediated antiviral signaling. A color version of this figure is available online.