title: DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA.
abstract: Programmed necrosis, like apoptosis, eliminates pathogen-infected cells as a component of host defense. Receptor-interacting protein kinase (RIP) 3 (also called RIPK3) mediates RIP homotypic interaction motif (RHIM)-dependent programmed necrosis induced by murine cytomegalovirus (MCMV) infection or death receptor activation and suppressed by the MCMV-encoded viral inhibitor of RIP activation (vIRA). We find that interferon-independent expression of DNA-dependent activator of interferon regulatory factors (DAI, also known as ZBP1 or DLM-1) sensitizes cells to virus-induced necrosis and that DAI knockdown or knockout cells are resistant to this death pathway. Importantly, as with RIP3(-/-) mice, vIRA mutant MCMV pathogenesis is restored in DAI(-/-) mice, consistent with a DAI-RIP3 complex being the natural target of vIRA. Thus, DAI interacts with RIP3 to mediate virus-induced necrosis analogous to the RIP1-RIP3 complex controlling death receptor-induced necroptosis. These studies unveil a role for DAI as the RIP3 partner mediating virus-induced necrosis.
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Upton
authors.forename: William J
authors.initials: WJ
authors.lastname: Kaiser
authors.forename: Edward S
authors.initials: ES
authors.lastname: Mocarski
mesh_terms: D000818:Animals; D017209:Apoptosis; D006023:Glycoproteins / Q000378:metabolism / Q000502:physiology*; D006566:Herpesviridae Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D054884:Host-Pathogen Interactions; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000821:virology; D016899:Interferon-beta / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism / Q000502:physiology; D018146:Muromegalovirus / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D041681:NIH 3T3 Cells; D009336:Necrosis / Q000378:metabolism / Q000821:virology*; D016601:RNA-Binding Proteins; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019562:Viral Load; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D006023:Glycoproteins; D046912:Multiprotein Complexes; D016328:NF-kappa B; D016601:RNA-Binding Proteins; D014764:Viral Proteins; C402632:Zbp1 protein, mouse; D016899:Interferon-beta; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse