title: Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense.
abstract: The receptor-interacting kinase-3 (RIP3) and its downstream substrate mixed lineage kinase domain-like protein (MLKL) have emerged as the key cellular components in programmed necrotic cell death. Receptors for the cytokines of tumor necrosis factor (TNF) family and Toll-like receptors (TLR) 3 and 4 are able to activate RIP3 through receptor-interacting kinase-1 and Toll/IL-1 receptor domain-containing adapter inducing IFN-β, respectively. This form of cell death has been implicated in the host-defense system. However, the molecular mechanisms that drive the activation of RIP3 by a variety of pathogens, other than the above-mentioned receptors, are largely unknown. Here, we report that human herpes simplex virus 1 (HSV-1) infection triggers RIP3-dependent necrosis. This process requires MLKL but is independent of TNF receptor, TLR3, cylindromatosis, and host RIP homotypic interaction motif-containing protein DNA-dependent activator of IFN regulatory factor. After HSV-1 infection, the viral ribonucleotide reductase large subunit (ICP6) interacts with RIP3. The formation of the ICP6-RIP3 complex requires the RHIM domains of both proteins. An HSV-1 ICP6 deletion mutant failed to cause effective necrosis of HSV-1-infected cells. Furthermore, ectopic expression of ICP6, but not RHIM mutant ICP6, directly activated RIP3/MLKL-mediated necrosis. Mice lacking RIP3 exhibited severely impaired control of HSV-1 replication and pathogenesis. Therefore, this study reveals a previously uncharacterized host antipathogen mechanism.
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China;
authors.forename: Xing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China;
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China;
authors.forename: Shan
authors.initials: S
authors.lastname: Liu
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China;
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Yu
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China;
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China;
authors.forename: Cuilin
authors.initials: C
authors.lastname: Shi
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China;
authors.forename: Wenhui
authors.initials: W
authors.lastname: He
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China;
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China;
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China;
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Emergency Medicine, First Affiliated Hospital, Soochow University, Suzhou 215006, China; and.
authors.forename: Lu
authors.initials: L
authors.lastname: Yu
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China;
authors.forename: Zhongxu
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China;
authors.forename: Qin
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China;
authors.forename: Lin
authors.initials: L
authors.lastname: Ge
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China;
authors.forename: Zili
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China;
authors.forename: Biqi
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Jiang
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China;
authors.forename: She
authors.initials: S
authors.lastname: Chen
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China; hesudan@suda.edu.cn.
authors.forename: Sudan
authors.initials: S
authors.lastname: He
mesh_terms: D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism; D000074749:Deubiquitinating Enzyme CYLD; D004789:Enzyme Activation; D006023:Glycoproteins / Q000378:metabolism; D006561:Herpes Simplex / Q000276:immunology / Q000473:pathology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000472:pathogenicity; D054884:Host-Pathogen Interactions / Q000276:immunology*; D006801:Humans; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism*; D053586:Virus Internalization; D014779:Virus Replication
chemical_list: D006023:Glycoproteins; D016328:NF-kappa B; D016601:RNA-Binding Proteins; D018124:Receptors, Tumor Necrosis Factor; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D014764:Viral Proteins; C402632:Zbp1 protein, mouse; C054366:herpes simplex virus type 1-protein ICP6; C570694:MLKL protein, mouse; D011494:Protein Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases
keywords: HSV-1; ICP6; MLKL; RIP3; programmed necrosis