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      Induction of GADD34 Is Necessary for dsRNA-Dependent Interferon-β Production and Participates in the Control of Chikungunya Virus Infection

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          Abstract

          Nucleic acid sensing by cells is a key feature of antiviral responses, which generally result in type-I Interferon production and tissue protection. However, detection of double-stranded RNAs in virus-infected cells promotes two concomitant and apparently conflicting events. The dsRNA-dependent protein kinase (PKR) phosphorylates translation initiation factor 2-alpha (eIF2α) and inhibits protein synthesis, whereas cytosolic DExD/H box RNA helicases induce expression of type I-IFN and other cytokines. We demonstrate that the phosphatase-1 cofactor, growth arrest and DNA damage-inducible protein 34 (GADD34/Ppp1r15a), an important component of the unfolded protein response (UPR), is absolutely required for type I-IFN and IL-6 production by mouse embryonic fibroblasts (MEFs) in response to dsRNA. GADD34 expression in MEFs is dependent on PKR activation, linking cytosolic microbial sensing with the ATF4 branch of the UPR. The importance of this link for anti-viral immunity is underlined by the extreme susceptibility of GADD34-deficient fibroblasts and neonate mice to Chikungunya virus infection.

          Author Summary

          Nucleic acids detection by multiple molecular sensors results in type-I interferon production, which protects cells and tissues from viral infections. At the intracellular level, the detection of double-stranded RNA by one of these sensors, the dsRNA-dependent protein kinase also leads to the profound inhibition of protein synthesis. We describe here that the inducible phosphatase 1 co-factor Ppp1r15a/GADD34, a well known player in the endoplasmic reticulum unfolded protein response (UPR), is activated during double-stranded RNA detection and is absolutely necessary to allow cytokine production in cells exposed to poly I:C or Chikungunya virus. Our data shows that the cellular response to nucleic acids can reveal unanticipated connections between innate immunity and fundamental stress pathways, such as the ATF4 branch of the UPR.

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          Most cited references 37

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          TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages.

          Sensors of pathogens, such as Toll-like receptors (TLRs), detect microbes to activate transcriptional programs that orchestrate adaptive responses to specific insults. Here we report that TLR4 and TLR2 specifically activated the endoplasmic reticulum (ER) stress sensor kinase IRE1alpha and its downstream target, the transcription factor XBP1. Previously described ER-stress target genes of XBP1 were not induced by TLR signaling. Instead, TLR-activated XBP1 was required for optimal and sustained production of proinflammatory cytokines in macrophages. Consistent with that finding, activation of IRE1alpha by ER stress acted in synergy with TLR activation for cytokine production. Moreover, XBP1 deficiency resulted in a much greater bacterial burden in mice infected with the TLR2-activating human intracellular pathogen Francisella tularensis. Our findings identify an unsuspected critical function for XBP1 in mammalian host defenses.
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            Innate recognition of viruses.

            Virus infection elicits potent responses in all cells intended to contain virus spread before intervention by the adaptive immune system. Central to this process is the virus-elicited production of type I interferons (IFNs) and other cytokines. The sensors involved in coupling recognition of viruses to the induction of the type I IFN genes have only recently been uncovered and include endosomal and cytosolic receptors for RNA and DNA. Here, we review their properties and discuss how their ability to recognize the unusual presence of atypical nucleic acids in particular subcellular compartments is used by the body to detect virus presence.
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              The endoplasmic reticulum stress response in immunity and autoimmunity.

              Many exogenous sources of stress can lead to cell death. In recent years, endogenous cellular sources of stress have also been identified, including the stress that arises from the accumulation of unfolded proteins within a cell's endoplasmic reticulum (ER). To counterbalance this type of ER stress, higher eukaryotic cells possess a three-pronged signal-transduction pathway termed the unfolded-protein response (UPR). This Review focuses on the role of the UPR in the mammalian immune system and how manipulation of this complex signalling pathway may be of therapeutic benefit in human disease.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                May 2012
                May 2012
                17 May 2012
                : 8
                : 5
                Affiliations
                [1 ]Centre d'Immunologie de Marseille-Luminy, UM2, Aix-Marseille Université, Marseille, France
                [2 ]INSERM, U1104, Marseille, France
                [3 ]CNRS, UMR 7280, Marseille, France
                [4 ]Institut Pasteur, ‘Microbes and host barriers’ Group, Paris, France
                [5 ]Inserm, Equipe avenir U604, Paris, France
                [6 ]Université Paris Descartes, Hôpital Necker-Enfants malades, Service des Maladies Infectieuses et Tropicales, Assistance Publique-Hôpitaux de Paris, Paris, France
                University of North Carolina at Chapel Hill, United States of America
                Author notes

                Conceived and designed the experiments: GC NC AD EG PP. Performed the experiments: GC TC NC AD DJ EKS TW VC. Analyzed the data: GC NC TC AD ML EG PP. Wrote the paper: GC NC AD ML EG PP.

                ¶ These authors also contributed equally to this work.

                Article
                PPATHOGENS-D-11-01110
                10.1371/journal.ppat.1002708
                3355096
                22615568
                0aba50b7-61f2-4e5a-9399-bb764195fd55
                Clavarino et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 17
                Categories
                Research Article
                Biology

                Infectious disease & Microbiology

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