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Review
. 2011 Sep;1(3):167-76.
doi: 10.1016/j.coviro.2011.04.004.

RIG-I like receptors and their signaling crosstalk in the regulation of antiviral immunity

Hilaroi J Ramos  1 , Micharl Gale Jr
Affiliations
Review

RIG-I like receptors and their signaling crosstalk in the regulation of antiviral immunity

Hilaroi J Ramos et al. Curr Opin Virol. 2011 Sep.

Abstract

During virus infection, multiple immune signaling pathways are triggered, both within the host cell and bystander cells of an infected tissue. These pathways act in concert to mediate innate antiviral immunity and to initiate the inflammatory response against infection. The RIG-I-like receptor (RLR) family of pattern recognition receptors (PRRs) is a group of cytosolic RNA helicase proteins that can identify viral RNA as nonself via binding to pathogen associated molecular patter (PAMP) motifs within RNA ligands that accumulate during virus infection. This interaction then leads to triggering of an innate antiviral response within the infected cells through RLR induction of downstream effector molecules such as type I interferon (IFN) and other pro-inflammatory cytokines that serve to induce antiviral and inflammatory gene expression within the local tissue. Cellular regulation of RLR signaling is a critical process that can direct the outcome of infection and is essential for governance of the overall immune response and avoidance of immune toxicity. Mechanisms of positive and negative regulation of RLR signaling have been identified that include signaling crosstalk between RLR pathways and Nuclear Oligomerization Domain (NOD)-Like Receptor (NLR) pathways and Caspase networks. Furthermore, many viruses have evolved mechanisms to target these pathways to promote enhanced replication and spread within the host. These virus-host interactions therefore carry important consequences for host immunity and viral pathogenesis. Understanding the pivotal role of RLRs in immune regulation and signaling crosstalk in antiviral immunity may provide new insights into therapeutic strategies for the control of virus infection and immunity.

Keywords: RIG-I-like receptors; immunity (author to check).

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Figures

Figure 1
Figure 1
Requirements for RIG-I and MDA5 in recognition of distinct viral families. Interactions between viruses and RIG-I and MDA5 are delineated by arrows. Red arrows depict known requirements for RIG-I in sensing viruses while blue arrows denote known requirements for MDA5. Of note, members of the Flaviviridae and Reoviridae can trigger both MDA5 and RIG-I activation. The RNA polymerase III pathway for generation of RIG-I ligands and the DNA viruses and bacteria, Legionella, known to activate this pathway are also shown.
Figure 2
Figure 2
RLR signaling and cellular regulation. RIG-I and MDA5 signal through the IPS-1 signalsome located at mitochondria, mitochondrial membranes or peroxisomes. Signaling proceeds through multiple adaptors and leads to the bifurcation and activation of IRF-3 and NF-κB via the kinases TBK-1 and IKKɛ. Cellular factors known to contribute to regulation of multiple stages of RLR signaling are depicted in the figure. Factors involved in ubiquitin mediated regulation are denoted in red text, factors which require direct interaction with RLR signaling components are depicted in blue text and factors with unknown mechanisms of regulation are shown in black text.
Figure 3
Figure 3
Viral regulation of RLR signaling. The RLR signalsome is shown including the RNA polymerase/RIG-I pathway for indirect recognition of cytosolic foreign DNA. Viral proteins known to block RLR signaling are shown with lines associating the specific factors they target. viruses or viral genus are denoted in parenthesis next to their specific proteins. Abbreviations: CCHFV (Crimean Congo Hemorrhagic Fever virus), BDV (Borna Disease virus), HTNV (Haantan virus).
Figure 4
Figure 4
RLR–NLR interactions in signaling against pathogens. The NOD2 signaling pathway for recognition of bacterial and viral PAMPs is shown on the left. NOD2 is triggered by bacterial MDP to activate NF-κB while ssRNA from RSV leads to activation of IRF-3 signaling. The RIG-I inflammasome is depicted on the right. Both RIG-I and MDA5 can interact with CARD9/BCL10 to activate NF-κB. This leads to induction of pro-IL-1β. RIG-I but not MDA5 can directly associate with ASC bifurcating NLR mediated activation of Caspase-1. This leads to cleavage of IL-1β and secretion from the cell.
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