RIG-I in RNA virus recognition

Abstract

Antiviral immunity is initiated upon host recognition of viral products via non-self molecular patterns known as pathogen-associated molecular patterns (PAMPs). Such recognition initiates signaling cascades that induce intracellular innate immune defenses and an inflammatory response that facilitates development of the acquired immune response. The retinoic acid-inducible gene I (RIG-I) and the RIG-I-like receptor (RLR) protein family are key cytoplasmic pathogen recognition receptors that are implicated in the recognition of viruses across genera and virus families, including functioning as major sensors of RNA viruses, and promoting recognition of some DNA viruses. RIG-I, the charter member of the RLR family, is activated upon binding to PAMP RNA. Activated RIG-I signals by interacting with the adapter protein MAVS leading to a signaling cascade that activates the transcription factors IRF3 and NF-κB. These actions induce the expression of antiviral gene products and the production of type I and III interferons that lead to an antiviral state in the infected cell and surrounding tissue. RIG-I signaling is essential for the control of infection by many RNA viruses. Recently, RIG-I crosstalk with other pathogen recognition receptors and components of the inflammasome has been described. In this review, we discuss the current knowledge regarding the role of RIG-I in recognition of a variety of virus families and its role in programming the adaptive immune response through cross-talk with parallel arms of the innate immune system, including how RIG-I can be leveraged for antiviral therapy.

Keywords: Infection; Innate immunity; Pathogen-associated molecular pattern; RIG-I; RIG-I-like receptor; RNA virus.

Graphical abstract

Fig. 1

RIG-I signaling pathway. (1) In resting cells RIG-I is maintained in a resting state in the cytosol characterized by a ‘closed fist’ conformation with the RD and CARD domains folded over the helicase domain. Interactions with LGP2 may be important for regulating RIG-I. (2) Upon recognition of an RNA ligand containing PAMP motif and exposed 5′ppp RIG-I is ubiquitinated and hydrolyzes ATP to promote a conformational change that holds the ligand PAMP RNA in the RNA binding groove of the RD. (3) Interactions with PACT, ZAPS, TRIM25 and 14-3-3ε lead to formation of a RIG-I translocase that moves from a soluble compartment in the cell to the mitochondrial associated membranes (MAM) where the complex engages MAVS for downstream signaling. The MAM is a specialized extension of outer mitochondria membrane (Mito) and endoplasmic reticulum (ER) that form a synapse to create an innate immune signaling platform. (4) CARD–CARD interactions between RIG-I and MAVS then initiate activation of the MAVS ‘signalosome’ which includes TRAF2, 3, and 6, TRADD, TANK, the IRF3 kinases TBK1 and/or IKKε, and the NF-κB kinase complex. (5) Signaling through these kinases activates IRF3 and NF-κB. (6) Phosphorylated IRF3 and activated NF-κB translocate to the nucleus and initiate transcription of genes encoding products with antiviral, proinflammatory, and immune-regulatory actions.

Fig. 2

Examples of known RIG-I PAMP RNAs with models of specific structures shown. (A) RNAfold predicted structure of measles virus leader RNA using Edmonson B strain sequence. (B) Influenza virus PAMPs found at genomic 5′ and 3′ nontranslated regions of the NS1 segment (adapted from Davis et al. (2012)). (C) Sendai virus defective-interfering (DI) particle structure (adapted from Martinez-Gil et al. (2013)). (D) RNAfold predicted structure of Hantavirus nucleoprotein mRNA using TPM strain sequence. (E) Reovirus genomic dsRNA with 5′pp motif identified as RIG-I PAMP in Goubau et al. (2014). (F) Hepatitis C virus genome with 3′ nontranslated region and poly-U/UC PAMP highlighted (adapted from Horner and Gale (2013)).