title: Mouse cytomegalovirus M36 and M45 death suppressors cooperate to prevent inflammation resulting from antiviral programmed cell death pathways.
abstract: The complex interplay between caspase-8 and receptor-interacting protein (RIP) kinase RIP 3 (RIPK3) driving extrinsic apoptosis and necroptosis is not fully understood. Murine cytomegalovirus triggers both apoptosis and necroptosis in infected cells; however, encoded inhibitors of caspase-8 activity (M36) and RIP3 signaling (M45) suppress these antiviral responses. Here, we report that this virus activates caspase-8 in macrophages to trigger apoptosis that gives rise to secondary necroptosis. Infection with double-mutant ΔM36/M45mutRHIM virus reveals a signaling pattern in which caspase-8 activates caspase-3 to drive apoptosis with subsequent RIP3-dependent activation of mixed lineage kinase domain-like (MLKL) leading to necroptosis. This combined cell death signaling is highly inflammatory, greater than either apoptosis induced by ΔM36 or necroptosis induced by M45mutRHIM virus. IL-6 production by macrophages is dramatically increased during double-mutant virus infection and correlates with faster antiviral responses in the host. Collaboratively, M36 and M45 target caspase-8 and RIP3 pathways together to suppress this proinflammatory cell death. This study reveals the effect of antiviral programmed cell death pathways on inflammation, shows that caspase-8 activation may go hand-in-hand with necroptosis in macrophages, and revises current understanding of independent and collaborative functions of M36 and M45 in blocking apoptotic and necroptotic cell death responses.
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322 ldaley@emory.edu mocarski@emory.edu.
authors.forename: Lisa P
authors.initials: LP
authors.lastname: Daley-Bauer
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Linda
authors.initials: L
authors.lastname: Roback
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Lynsey N
authors.initials: LN
authors.lastname: Crosby
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: A Louise
authors.initials: AL
authors.lastname: McCormick
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: William J
authors.initials: WJ
authors.lastname: Kaiser
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322 ldaley@emory.edu mocarski@emory.edu.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Mocarski
mesh_terms: D000818:Animals; D017209:Apoptosis; D053181:Caspase 8 / Q000235:genetics / Q000276:immunology; D006566:Herpesviridae Infections / Q000276:immunology / Q000503:physiopathology / Q000662:veterinary* / Q000821:virology; D054884:Host-Pathogen Interactions; D051379:Mice; D018146:Muromegalovirus / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D012264:Ribonucleotide Reductases / Q000235:genetics / Q000378:metabolism*; D012376:Rodent Diseases / Q000235:genetics / Q000276:immunology / Q000503:physiopathology* / Q000821:virology; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C000627184:M36 protein, mouse cytomegalovirus; D014764:Viral Proteins; D012264:Ribonucleotide Reductases; C422747:m45 protein, Mouse cytomegalovirus 1; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D053181:Caspase 8
keywords: MCMV; RIP3 kinase; caspase-8; cell death; inflammation