title: Necroptosis: The Trojan horse in cell autonomous antiviral host defense.
abstract: Herpesviruses suppress cell death to assure sustained infection in their natural hosts. Murine cytomegalovirus (MCMV) encodes suppressors of apoptosis as well as M45-encoded viral inhibitor of RIP activation (vIRA) to block RIP homotypic interaction motif (RHIM)-signaling and recruitment of RIP3 (also called RIPK3), to prevent necroptosis. MCMV and human cytomegalovirus encode a viral inhibitor of caspase (Casp)8 activation to block apoptosis, an activity that unleashes necroptosis. Herpes simplex virus (HSV)1 and HSV2 incorporate both RHIM and Casp8 suppression strategies within UL39-encoded ICP6 and ICP10, respectively, which are herpesvirus-conserved homologs of MCMV M45. Both HSV proteins sensitize human cells to necroptosis by blocking Casp8 activity while preventing RHIM-dependent RIP3 activation and death. In mouse cells, HSV1 ICP6 interacts with RIP3 and, surprisingly, drives necroptosis. Thus, herpesviruses have illuminated the contribution of necoptosis to host defense in the natural host as well as its potential to restrict cross-species infections in nonnatural hosts.
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: mocarski@emory.edu.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Mocarski
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Kaiser
mesh_terms: D000818:Animals; D017209:Apoptosis; D002468:Cell Physiological Phenomena; D006564:Herpesviridae / Q000276:immunology*; D054884:Host-Pathogen Interactions; D006801:Humans; D009336:Necrosis
keywords: FADD; Programmed necrosis; Ribonucleotide reductase; Serine/threonine protein kinase; cFLIP
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