title: Suppression of RIP3-dependent necroptosis by human cytomegalovirus.
abstract: Necroptosis is an alternate programmed cell death pathway that is unleashed by caspase-8 compromise and mediated by receptor-interacting protein kinase 3 (RIP3). Murine cytomegalovirus (CMV) and herpes simplex virus (HSV) encode caspase-8 inhibitors that prevent apoptosis together with competitors of RIP homotypic interaction motif (RHIM)-dependent signal transduction to interrupt the necroptosis. Here, we show that pro-necrotic murine CMV M45 mutant virus drives virus-induced necroptosis during nonproductive infection of RIP3-expressing human fibroblasts, whereas WT virus does not. Thus, M45-encoded RHIM competitor, viral inhibitor of RIP activation, sustains viability of human cells like it is known to function in infected mouse cells. Importantly, human CMV is shown to block necroptosis induced by either TNF or M45 mutant murine CMV in RIP3-expressing human cells. Human CMV blocks TNF-induced necroptosis after RIP3 activation and phosphorylation of the mixed lineage kinase domain-like (MLKL) pseudokinase. An early, IE1-regulated viral gene product acts on a necroptosis step that follows MLKL phosphorylation prior to membrane leakage. This suppression strategy is distinct from RHIM signaling competition by murine CMV or HSV and interrupts an execution process that has not yet been fully elaborated.
authors.affiliation: From the Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Shinya
authors.initials: S
authors.lastname: Omoto
authors.affiliation: From the Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Guo
authors.affiliation: From the Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Ganesh R
authors.initials: GR
authors.lastname: Talekar
authors.affiliation: From the Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Linda
authors.initials: L
authors.lastname: Roback
authors.affiliation: From the Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: William J
authors.initials: WJ
authors.lastname: Kaiser
authors.affiliation: From the Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322 mocarski@emory.edu.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Mocarski
mesh_terms: D000818:Animals; D003587:Cytomegalovirus / Q000378:metabolism / Q000502:physiology*; D019143:Evolution, Molecular; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000821:virology; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D051379:Mice; D018146:Muromegalovirus / Q000502:physiology; D009336:Necrosis; D010766:Phosphorylation; D021381:Protein Transport; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction; D014161:Transduction, Genetic
chemical_list: D017874:Immediate-Early Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases
keywords: Caspase; Herpesvirus; Human CMV; Innate Immunity; MCMV; Necrosis (Necrotic Death); Programmed Necrosis; Regulated Cell Death; Tumor Necrosis Factor (TNF)