title: Viral RNA at Two Stages of Reovirus Infection Is Required for the Induction of Necroptosis.
abstract: Necroptosis, a regulated form of necrotic cell death, requires the activation of the RIP3 kinase. Here, we identify that infection of host cells with reovirus can result in necroptosis. We find that necroptosis requires sensing of the genomic RNA within incoming virus particles via cytoplasmic RNA sensors to produce type I interferon (IFN). While these events that occur prior to thede novosynthesis of viral RNA are required for the induction of necroptosis, they are not sufficient. The induction of necroptosis also requires late stages of reovirus infection. Specifically, efficient synthesis of double-stranded RNA (dsRNA) within infected cells is required for necroptosis. These data indicate that viral RNA interfaces with host components at two different stages of infection to induce necroptosis. This work provides new molecular details about events in the viral replication cycle that contribute to the induction of necroptosis following infection with an RNA virus.IMPORTANCEAn appreciation of how cell death pathways are regulated following viral infection may reveal strategies to limit tissue destruction and prevent the onset of disease. Cell death following virus infection can occur by apoptosis or a regulated form of necrosis known as necroptosis. Apoptotic cells are typically disposed of without activating the immune system. In contrast, necroptotic cells alert the immune system, resulting in inflammation and tissue damage. While apoptosis following virus infection has been extensively investigated, how necroptosis is unleashed following virus infection is understood for only a small group of viruses. Here, using mammalian reovirus, we highlight the molecular mechanism by which infection with a dsRNA virus results in necroptosis.
authors.affiliation: Department of Biology, Indiana University, Bloomington, Indiana, USA.
authors.forename: Angela K
authors.initials: AK
authors.lastname: Berger
authors.affiliation: Department of Biology, Indiana University, Bloomington, Indiana, USA.
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Hiller
authors.affiliation: Department of Biology, Indiana University, Bloomington, Indiana, USA.
authors.forename: Deepti
authors.initials: D
authors.lastname: Thete
authors.affiliation: Department of Biology, Indiana University, Bloomington, Indiana, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Snyder
authors.affiliation: Department of Molecular Biosciences, LaMontagne Center for Infectious Disease, University of Texas, Austin, Texas, USA.
authors.forename: Encarnacion
authors.initials: E
authors.lastname: Perez
authors.affiliation: Department of Molecular Biosciences, LaMontagne Center for Infectious Disease, University of Texas, Austin, Texas, USA.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Upton
authors.affiliation: Department of Biology, Indiana University, Bloomington, Indiana, USA pdanthi@indiana.edu.
authors.forename: Pranav
authors.identifier: http://orcid.org/0000-0001-6199-6022
authors.initials: P
authors.lastname: Danthi
mesh_terms: D000818:Animals; D016923:Cell Death; D002460:Cell Line; D005347:Fibroblasts / Q000276:immunology / Q000502:physiology / Q000821:virology; D054884:Host-Pathogen Interactions; D007113:Immunity, Innate; D051379:Mice; D012367:RNA, Viral / Q000378:metabolism*; D012087:Reoviridae / Q000276:immunology* / Q000502:physiology*
chemical_list: D012367:RNA, Viral
keywords: cell death; innate immunity; necroptosis; reovirus