title: Induction of necroptotic cell death by viral activation of the RIG-I or STING pathway.
abstract: Necroptosis is a form of necrotic cell death that requires the activity of the death domain-containing kinase RIP1 and its family member RIP3. Necroptosis occurs when RIP1 is deubiquitinated to form a complex with RIP3 in cells deficient in the death receptor adapter molecule FADD or caspase-8. Necroptosis may play a role in host defense during viral infection as viruses like vaccinia can induce necroptosis while murine cytomegalovirus encodes a viral inhibitor of necroptosis. To see how general the interplay between viruses and necroptosis is, we surveyed seven different viruses. We found that two of the viruses tested, Sendai virus (SeV) and murine gammaherpesvirus-68 (MHV68), are capable of inducing dramatic necroptosis in the fibrosarcoma L929 cell line. We show that MHV68-induced cell death occurs through the cytosolic STING sensor pathway in a TNF-dependent manner. In contrast, SeV-induced death is mostly independent of TNF. Knockdown of the RNA sensing molecule RIG-I or the RIP1 deubiquitin protein, CYLD, but not STING, rescued cells from SeV-induced necroptosis. Accompanying necroptosis, we also find that wild type but not mutant SeV lacking the viral proteins Y1 and Y2 result in the non-ubiquitinated form of RIP1. Expression of Y1 or Y2 alone can suppress RIP1 ubiquitination but CYLD is dispensable for this process. Instead, we found that Y1 and Y2 can inhibit cIAP1-mediated RIP1 ubiquitination. Interestingly, we also found that SeV infection of B6 RIP3-/-mice results in increased inflammation in the lung and elevated SeV-specific T cells. Collectively, these data identify viruses and pathways that can trigger necroptosis and highlight the dynamic interplay between pathogen-recognition receptors and cell death induction.
authors.affiliation: Department of Molecular and Cell Biology and Cancer Research Laboratory, 469 LSA, University of California, Berkeley, CA 94720-3200, USA.
authors.forename: Suruchi N
authors.identifier: 0000-0003-0863-3593
authors.initials: SN
authors.lastname: Schock
authors.affiliation: Department of Molecular and Cell Biology and Cancer Research Laboratory, 469 LSA, University of California, Berkeley, CA 94720-3200, USA.
authors.forename: Neha V
authors.initials: NV
authors.lastname: Chandra
authors.affiliation: Department of Molecular and Cell Biology and Cancer Research Laboratory, 469 LSA, University of California, Berkeley, CA 94720-3200, USA.
authors.forename: Yuefang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Virology, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Irie
authors.affiliation: Division of Microbiology and Infectious Diseases, Department of Pathology, Shiga University of Medical Science, Seta, Otsu, Shiga 520-2192, Japan.
authors.forename: Yoshinori
authors.identifier: 0000-0002-3275-3336
authors.initials: Y
authors.lastname: Kitagawa
authors.affiliation: Division of Microbiology and Infectious Diseases, Department of Pathology, Shiga University of Medical Science, Seta, Otsu, Shiga 520-2192, Japan.
authors.forename: Bin
authors.initials: B
authors.lastname: Gotoh
authors.affiliation: Department of Molecular and Cell Biology and Cancer Research Laboratory, 469 LSA, University of California, Berkeley, CA 94720-3200, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Coscoy
authors.affiliation: Department of Molecular and Cell Biology and Cancer Research Laboratory, 469 LSA, University of California, Berkeley, CA 94720-3200, USA.
authors.forename: Astar
authors.initials: A
authors.lastname: Winoto
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000071457:DEAD Box Protein 58 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000074749:Deubiquitinating Enzyme CYLD; D018142:Gammaherpesvirinae / Q000502:physiology*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D029082:Sendai virus / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D054875:Ubiquitination / Q000187:drug effects; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014775:Virus Activation; D000099197:STING Protein
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D003546:Cysteine Endopeptidases; D000071457:DEAD Box Protein 58; D000074749:Deubiquitinating Enzyme CYLD; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; C530855:Sting1 protein, mouse; D000099197:STING Protein; C484771:benzyloxycarbonyl-valyl-aspartic acid fluoromethyl ketone; C485615:Ripk3 protein, mouse; C511601:CYLD protein, mouse; C503356:Ddx58 protein, mouse