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      Depletion of RIPK1 in hepatocytes exacerbates liver damage in fulminant viral hepatitis

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          Abstract

          The protein kinase RIPK1 plays a crucial role at the crossroad of stress-induced signaling pathways that affects cell’s decision to live or die. The present study aimed to define the role of RIPK1 in hepatocytes during fulminant viral hepatitis, a worldwide syndrome mainly observed in hepatitis B virus (HBV) infected patients. Mice deficient for RIPK1, specifically in liver parenchymal cells ( Ripk1 LPC-KO) and their wild-type littermates ( Ripk1 fl/fl), were challenged by either the murine hepatitis virus type 3 (MHV3) or poly I:C, a synthetic analog of double-stranded RNA mimicking viral pathogen-associated molecular pattern. Ripk1 LPC-KO mice developed more severe symptoms at early stage of the MHV3-induced fulminant hepatitis. Similarly, administration of poly I:C only triggered increase of systemic transaminases in Ripk1 LPC-KO mice, reflecting liver damage through induced apoptosis as illustrated by cleaved-caspase 3 labeling of liver tissue sections. Neutralization of TNF-α or prior depletion of macrophages were able to prevent the appearance of apoptosis of hepatocytes in poly I:C-challenged Ripk1 LPC-KO mice. Moreover, poly I:C never induced direct hepatocyte death in primary culture whatever the murine genotype, while it always stimulated an anti-viral response. Our investigations demonstrated that RIPK1 protects hepatocytes from TNF-α secreted from macrophages during viral induced fulminant hepatitis. These data emphasize the potential worsening risks of an HBV infection in people with polymorphism or homozygous amorphic mutations already described for the RIPK1 gene.

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          Mechanisms of Coronavirus Cell Entry Mediated by the Viral Spike Protein

          Coronaviruses are enveloped positive-stranded RNA viruses that replicate in the cytoplasm. To deliver their nucleocapsid into the host cell, they rely on the fusion of their envelope with the host cell membrane. The spike glycoprotein (S) mediates virus entry and is a primary determinant of cell tropism and pathogenesis. It is classified as a class I fusion protein, and is responsible for binding to the receptor on the host cell as well as mediating the fusion of host and viral membranes—A process driven by major conformational changes of the S protein. This review discusses coronavirus entry mechanisms focusing on the different triggers used by coronaviruses to initiate the conformational change of the S protein: receptor binding, low pH exposure and proteolytic activation. We also highlight commonalities between coronavirus S proteins and other class I viral fusion proteins, as well as distinctive features that confer distinct tropism, pathogenicity and host interspecies transmission characteristics to coronaviruses.
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            The death domain kinase RIP mediates the TNF-induced NF-kappaB signal.

            The death domain serine/threonine kinase RIP interacts with the death receptors Fas and tumor necrosis receptor 1 (TNFR1). In vitro, RIP stimulates apoptosis, SAPK/JNK, and NF-kappaB activation. To define the physiologic role(s) that RIP plays in regulating apoptosis in vivo, we introduced a rip null mutation in mice through homologous recombination. RIP-deficient mice appear normal at birth but fail to thrive, displaying extensive apoptosis in both the lymphoid and adipose tissue and dying at 1-3 days of age. In contrast to a normal thymic anti-Fas response, rip-/- cells are highly sensitive to TNFalpha-induced cell death. Sensitivity to TNFalpha-mediated cell death in rip-/- cells is accompanied by a failure to activate the transcription factor NF-kappaB.
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              RIP kinases: key decision makers in cell death and innate immunity.

              Innate immunity represents the first line of defence against invading pathogens. It consists of an initial inflammatory response that recruits white blood cells to the site of infection in an effort to destroy and eliminate the pathogen. Some pathogens replicate within host cells, and cell death by apoptosis is an important effector mechanism to remove the replication niche for such microbes. However, some microbes have evolved evasive strategies to block apoptosis, and in these cases host cells may employ further countermeasures, including an inflammatory form of cell death know as necroptosis. This review aims to highlight the importance of the RIP kinase family in controlling these various defence strategies. RIP1 is initially discussed as a key component of death receptor signalling and in the context of dictating whether a cell triggers a pathway of pro-inflammatory gene expression or cell death by apoptosis. The molecular and functional interplay of RIP1 and RIP3 is described, especially with respect to mediating necroptosis and as key mediators of inflammation. The function of RIP2, with particular emphasis on its role in NOD signalling, is also explored. Special attention is given to emphasizing the physiological and pathophysiological contexts for these various functions of RIP kinases.
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                Author and article information

                Contributors
                +33) (0)2 23 23 48 62 , jacques.leseyec@univ-rennes1.fr
                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group UK (London )
                2041-4889
                8 January 2019
                8 January 2019
                January 2019
                : 10
                : 1
                : 12
                Affiliations
                [1 ]Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S, 1085 Rennes, France
                [2 ]Department of Clinical Sciences, College of Veterinary and Animal Sciences, Jhang, Pakistan
                [3 ]ISNI 0000000419368729, GRID grid.21729.3f, Present Address: Department of Medicine, , Columbia University, ; New York, NY USA
                Article
                1277
                10.1038/s41419-018-1277-3
                6325114
                30622241
                f25e871c-934e-49c7-8833-1618428c38fd
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 31 July 2018
                : 21 November 2018
                : 3 December 2018
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001677, Institut National de la Santé et de la Recherche Médicale (National Institute of Health and Medical Research);
                Funded by: FundRef https://doi.org/10.13039/501100004099, Ligue Contre le Cancer;
                Funded by: FundRef https://doi.org/10.13039/501100004681, Higher Education Commission, Pakistan (HEC);
                Funded by: FundRef https://doi.org/10.13039/501100007525, Université de Rennes 1 (University of Rennes 1);
                Funded by: FundRef https://doi.org/10.13039/501100002915, Fondation pour la Recherche Médicale (Foundation for Medical Research in France);
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                © The Author(s) 2019

                Cell biology
                Cell biology

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