title: Herpes simplex virus suppresses necroptosis in human cells.
abstract: Herpes simplex virus (HSV)-1 and HSV-2 are significant human pathogens causing recurrent disease. During infection, HSV modulates cell death pathways using the large subunit (R1) of ribonucleotide reductase (RR) to suppress apoptosis by binding to and blocking caspase-8. Here, we demonstrate that HSV-1 and HSV-2 R1 proteins (ICP6 and ICP10, respectively) also prevent necroptosis in human cells by inhibiting the interaction between receptor-interacting protein kinase 1 (RIP1) and RIP3, a key step in tumor necrosis factor (TNF)-induced necroptosis. We show that suppression of this cell death pathway requires an N-terminal RIP homotypic interaction motif (RHIM) within R1, acting in concert with the caspase-8-binding domain, which unleashes necroptosis independent of RHIM function. Thus, necroptosis is a human host defense pathway against two important viral pathogens that naturally subvert multiple death pathways via a single evolutionarily conserved gene product.
authors: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Hongyan
authors: H
authors: Guo
authors: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Shinya
authors: S
authors: Omoto
authors: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors: Philip A
authors: PA
authors: Harris
authors: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors: Joshua N
authors: JN
authors: Finger
authors: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors: John
authors: J
authors: Bertin
authors: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors: Peter J
authors: PJ
authors: Gough
authors: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: wkaiser@emory.edu.
authors: William J
authors: WJ
authors: Kaiser
authors: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: mocarski@emory.edu.
authors: Edward S
authors: ES
authors: Mocarski
mesh_terms: D053181:Caspase 8 / Q000378:metabolism; D016923:Cell Death; D018259:Herpesvirus 1, Human / Q000276:immunology* / Q000502:physiology; D018258:Herpesvirus 2, Human / Q000276:immunology* / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D028861:Nuclear Pore Complex Proteins / Q000037:antagonists & inhibitors*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D012264:Ribonucleotide Reductases / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication
chemical_list: C119724:AGFG1 protein, human; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; D014764:Viral Proteins; D012264:Ribonucleotide Reductases; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C505530:CASP8 protein, human; D053181:Caspase 8