Immune Signaling by RIG-I-like Receptors

Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195-7650, USA.
Immunity (Impact Factor: 21.56). 05/2011; 34(5):680-92. DOI: 10.1016/j.immuni.2011.05.003
Source: PubMed

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.

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    • "IFN produced and secreted as a result of the RLR cascade binds to the IFN receptor to regulate JAK- STAT signaling and the ISGF3-dependent expression of interferonstimulated genes (ISGs) encoding proteins, such as Mx1 [16e18], which possess direct antiviral activity [4] [19]. In addition, virus infection and signaling through the RLRs also induce the expression of various proinflammatory cytokines, for instance IL-1b [20], to control infection [4]. "
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    ABSTRACT: Melanoma differentiation-associated gene 5 (MDA5) is a member of retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family which can initiate type I IFN expression in response to RNA virus infection. In this study, we constructed six mutants of Ctenopharyngodon idella MDA5 (CiMAD5) overexpression plasmids and generated stable transfected Ctenopharyngodon idella kidney (CIK) cell lines to study the function of different domains of CiMAD5. After ploy(I:C) stimulation, the downstream genes of CiMDA5 in transfected cells was repressed. Overexpression of CiMDA5 or its variant repressed the replication of grass carp reovirus (GCRV) in CIK cells and decreased the viral titer of GCRV more or less compared to that in control cells. After GCRV or bacterial pathogen-associated molecular patterns (PAMPs) stimulation, overexpression of CiMDA5 or CARD domain significantly induced the expression of CiIFN-I, CiIL-1β and CiMx1. The deletion of Helicase or RD domain reduced the inductive effect of CiMDA5 on CiIFN-I, CiIL-1β and CiMx1 expression. RD overexpression resulted in an enhanced expression of CiIFN-I, CiIL-1β and CiMx1. These observations collectively demonstrate that, in CIK cells, after GCRV or bacterial PAMPs stimulation, CARD domain alone can mediate signaling; Helicase or RD domain alone is negatively regulates CARD function by intramolecular interaction with CARD. However, RD domain acts as an enhancer by intermolecular interaction. These results enlarge the response spectrum of MDA5 and contribute to a further understanding of the functions of MDA5 and its domains in evolution. Copyright © 2015. Published by Elsevier Ltd.
    Fish &amp Shellfish Immunology 08/2015; 46(2). DOI:10.1016/j.fsi.2015.08.005 · 2.67 Impact Factor
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    • "Complex assembly is responsible for the activation of the IKK and IKK-like kinases, which activate necrosis factor (NF)-kB and IRF3/7, respectively, resulting in the formation of the interferon beta (IFN-B) enhanceosome (Loo and Gale, 2011). Transcriptional induction of IFNB results in both autocrine and paracrine activation of the JAK/STAT pathway and the coordinated upregulation of $500 interferon-stimulated genes (ISGs) (Loo and Gale, 2011). In addition, many ISGs can also be directly induced in response to virus infection as a result of PRR detection and IRF3/7 activation (Honda et al., 2005; Schmid et al., 2010). "
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    ABSTRACT: Responding to an influenza A virus (IAV) infection demands an effective intrinsic cellular defense strategy to slow replication. To identify contributing host factors to this defense, we exploited the host microRNA pathway to perform an in vivo RNAi screen. To this end, IAV, lacking a functional NS1 antagonist, was engineered to encode individual siRNAs against antiviral host genes in an effort to rescue attenuation. This screening platform resulted in the enrichment of strains targeting virus-activated transcription factors, specific antiviral effectors, and intracellular pattern recognition receptors (PRRs). Interestingly, in addition to RIG-I, the PRR for IAV, a virus with the capacity to silence MDA5 also emerged as a dominant strain in wild-type, but not in MDA5-deficient mice. Transcriptional profiling of infected knockout cells confirmed RIG-I to be the primary PRR for IAV but implicated MDA5 as a significant contributor to the cellular defense against influenza A virus. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 06/2015; 11(11). DOI:10.1016/j.celrep.2015.05.032 · 8.36 Impact Factor
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    • "The innate immune system is essential for controlling viral infection. Cytoplasmic viral RNA and polyI:C are recognized by RIG-I-like receptors including RIG-I and MDA5, which trigger the induction of type I and III interferons (IFNs) and other inflammatory cytokines via the MAVS adaptor molecule (also called IPS-1, Cardif, and VISA) (Loo and Gale, 2011). MAVS activates TBK1 protein kinase, leading to autophosphorylation of TBK1 (Soulat et al., 2008). "
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    ABSTRACT: RIG-I-mediated type I interferon (IFN) production and nuclease-mediated viral RNA degradation are essential for antiviral innate immune responses. DDX60 is an IFN-inducible cytoplasmic helicase. Here, we report that DDX60 is a sentinel for both RIG-I activation and viral RNA degradation. We show that DDX60 is an upstream factor of RIG-I that activates RIG-I signaling in a ligand-specific manner. DDX60 knockout attenuates RIG-I signaling and significantly reduces virus-induced type I IFN production in vivo. In addition, we show that DDX60 is involved in RIG-I-independent viral RNA degradation. DDX60 and RIG-I adaptor MAVS double-knockout mice reveal a role for DDX60-dependent RNA degradation in antiviral responses. Several viruses induced DDX60 phosphorylation via epidermal growth factor receptor (EGFR), leading to attenuation of the DDX60 antiviral activities. Our results define DDX60 as a sentinel for cytoplasmic antiviral response, which is counteracted by virus-mediated EGF receptor activation. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 05/2015; 12(8). DOI:10.1016/j.celrep.2015.04.047 · 8.36 Impact Factor
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