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      CASPASE 8 inhibits programmed necrosis by processing CYLD

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          Abstract

          CASPASE 8 initiates apoptosis downstream of TNF death receptors by undergoing autocleavage and processing the executioner CASPASE 3 1 . However, the dominant function of CASPASE 8 is to transmit a pro-survival signal that suppresses programmed necrosis (or necroptosis) mediated by RIPK1 and RIPK3 26 during embryogenesis and hematopoiesis 79 . Suppression of necrotic cell death by CASPASE 8 requires its catalytic activity but not the autocleavage essential for apoptosis 10 , however, the key substrate processed by CASPASE 8 to block necrosis has been elusive. A key substrate must meet three criteria: (1) it must be essential for programmed necrosis; (2) it must be cleaved by CASPASE 8 in situations where CASPASE 8 is blocking necrosis; and (3) mutation of the CASPASE 8 processing site on the substrate should convert a pro-survival response to necrotic death without the need for CASPASE 8 inhibition. We now identify CYLD as a novel substrate for CASPASE 8 that satisfies these criteria. Upon TNF stimulation, CASPASE 8 cleaves CYLD to generate a survival signal. In contrast, loss of CASPASE 8 prevented CYLD degradation resulting in necrotic death. A CYLD substitution mutation at D215 that cannot be cleaved by CASPASE 8 switches cell survival to necrotic cell death in response to TNF.

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          Most cited references21

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          Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway.

          Stimulation of death receptors by agonists such as FasL and TNFalpha activates apoptotic cell death in apoptotic-competent conditions or a type of necrotic cell death dependent on RIP1 kinase, termed necroptosis, in apoptotic-deficient conditions. In a genome-wide siRNA screen for regulators of necroptosis, we identify a set of 432 genes that regulate necroptosis, a subset of 32 genes that act downstream and/or as regulators of RIP1 kinase, 32 genes required for death-receptor-mediated apoptosis, and 7 genes involved in both necroptosis and apoptosis. We show that the expression of subsets of the 432 genes is enriched in the immune and nervous systems, and cellular sensitivity to necroptosis is regulated by an extensive signaling network mediating innate immunity. Interestingly, Bmf, a BH3-only Bcl-2 family member, is required for death-receptor-induced necroptosis. Our study defines a cellular signaling network that regulates necroptosis and the molecular bifurcation that controls apoptosis and necroptosis.
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            The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response.

            On detecting viral RNAs, the RNA helicase retinoic acid-inducible gene I (RIG-I) activates the interferon regulatory factor 3 (IRF3) signalling pathway to induce type I interferon (IFN) gene transcription. How this antiviral signalling pathway might be negatively regulated is poorly understood. Microarray and bioinformatic analysis indicated that the expression of RIG-I and that of the tumour suppressor CYLD (cylindromatosis), a deubiquitinating enzyme that removes Lys 63-linked polyubiquitin chains, are closely correlated, suggesting a functional association between the two molecules. Ectopic expression of CYLD inhibits the IRF3 signalling pathway and IFN production triggered by RIG-I; conversely, CYLD knockdown enhances the response. CYLD removes polyubiquitin chains from RIG-I as well as from TANK binding kinase 1 (TBK1), the kinase that phosphorylates IRF3, coincident with an inhibition of the IRF3 signalling pathway. Furthermore, CYLD protein level is reduced in the presence of tumour necrosis factor and viral infection, concomitant with enhanced IFN production. These findings show that CYLD is a negative regulator of RIG-I-mediated innate antiviral response.
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              Mitochondrial cell death effectors.

              Programmed cell death (apoptosis) is crucial for embryogenesis and tissue homeostasis. Deregulated apoptosis leads to immunodeficiency, autoimmune disorders or cancer. The two main routes to apoptosis are the extrinsic and intrinsic (mitochondrial) pathways. Both involve caspase activation that leads to the cleavage of multiple intracellular substrates [1,9]. This review highlights recent advances in our understanding of the intrinsic pathway. We describe how BCL-2-family members preserve or disrupt mitochondrial integrity, the contribution of BH3-only proteins to this process, and the importance of cytotoxic factors released by the mitochondria. The growing evidence that the intrinsic pathway is crucial for tumourigenesis makes this an intriguing field. In particular, the finding that BCL-2 homologues are inhibited by BH3-only proteins may have future therapeutic applications.
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                Author and article information

                Journal
                100890575
                21417
                Nat Cell Biol
                Nat. Cell Biol.
                Nature Cell Biology
                1465-7392
                1476-4679
                16 September 2011
                30 October 2011
                01 June 2012
                : 13
                : 12
                : 1437-1442
                Affiliations
                [1 ]Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029, U.S.A.
                [2 ]Dept. of Immunology, St Jude’s Children’s Research Hospital, Memphis, TN 38105, U.S.A.
                [3 ]Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, U.S.A.
                [4 ]Department of Laboratory Medicine, Clinical Research Center, Lund University, SE-205 Malmo, Sweden
                Author notes
                [* ] Contact Information Correspondence: marie.a.odonnell@ 123456mssm.edu (M.A.O’D.), adrian.ting@ 123456mssm.edu (A.T.T.)
                [5]

                Current address: Laboratory of Cellular Biology, Centro de Investigacion Principe Felipe, Valencia, Spain

                [6]

                These authors contributed equally to this work.

                Article
                nihpa325384
                10.1038/ncb2362
                3229661
                22037414
                70840c90-dc1b-40b4-aacf-a00b60507651

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                History
                Funding
                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: R01 GM052735-11 || GM
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI044828-13 || AI
                Categories
                Article

                Cell biology
                Cell biology

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