Abstract
Programmed necrosis mediated by receptor interacting protein kinase (RIP)3 (also called RIPK3) has emerged as an alternate death pathway triggered by TNF family death receptors, pathogen sensors, IFNRs, Ag-specific TCR activation, and genotoxic stress. Necrosis leads to cell leakage and acts as a "trap door," eliminating cells that cannot die by apoptosis because of the elaboration of pathogen-encoded caspase inhibitors. Necrotic signaling requires RIP3 binding to one of three partners-RIP1, DAI, or TRIF-via a common RIP homotypic interaction motif. Once activated, RIP3 kinase targets the pseudokinase mixed lineage kinase domain-like to drive cell lysis. Although necrotic and apoptotic death can enhance T cell cross-priming during infection, mice that lack these extrinsic programmed cell death pathways are able to produce Ag-specific T cells and control viral infection. The entwined relationship of apoptosis and necrosis evolved in response to pathogen-encoded suppressors to support host defense and contribute to inflammation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Adaptor Proteins, Vesicular Transport / genetics
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Adaptor Proteins, Vesicular Transport / immunology
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Amino Acid Motifs
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Animals
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Apoptosis / genetics
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Apoptosis / immunology
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Capsid Proteins / genetics
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Capsid Proteins / immunology*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / immunology
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GTPase-Activating Proteins / genetics
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GTPase-Activating Proteins / immunology
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Glycoproteins / genetics
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Glycoproteins / immunology
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Humans
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Immune Tolerance*
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Inflammation / genetics
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Inflammation / immunology
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Mice
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Necrosis / genetics
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Necrosis / immunology
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Necrosis / pathology
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Nuclear Pore Complex Proteins / genetics
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Nuclear Pore Complex Proteins / immunology
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / immunology
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Receptor-Interacting Protein Serine-Threonine Kinases / genetics
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Receptor-Interacting Protein Serine-Threonine Kinases / immunology
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T-Lymphocytes / immunology*
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T-Lymphocytes / pathology
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Virus Diseases / genetics
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Virus Diseases / immunology*
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Virus Diseases / pathology
Substances
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AGFG1 protein, human
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Adaptor Proteins, Vesicular Transport
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Capsid Proteins
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DNA-Binding Proteins
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GTPase-Activating Proteins
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Glycoproteins
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Nuclear Pore Complex Proteins
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RNA-Binding Proteins
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Ralbp1 protein, mouse
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TICAM-1 protein, mouse
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TICAM1 protein, human
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ZBP1 protein, human
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Zbp1 protein, mouse
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RIPK3 protein, human
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Receptor-Interacting Protein Serine-Threonine Kinases
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Ripk3 protein, mouse