title: Subversion of autophagy by Kaposi's sarcoma-associated herpesvirus impairs oncogene-induced senescence.
abstract: Acute oncogenic stress can activate autophagy and facilitate permanent arrest of the cell cycle through a failsafe mechanism known as oncogene-induced senescence (OIS). Kaposi's sarcoma-associated herpesvirus (KSHV) proteins are known to subvert autophagic pathways, but the link to Kaposi's sarcoma pathogenesis is unclear. We find that oncogenic assault caused by latent KSHV infection elicits DNA damage responses (DDRs) characteristic of OIS, yet infected cells display only modest levels of autophagy and fail to senesce. These aberrant responses result from the combined activities of tandemly expressed KSHV v-cyclin and v-FLIP proteins. v-Cyclin deregulates the cell cycle, triggers DDRs, and if left unchecked can promote autophagy and senescence. However, during latency v-FLIP blocks v-cyclin-induced autophagy and senescence in a manner that requires intact v-FLIP ATG3-binding domains. Together, these data reveal a coordinated viral gene expression program that usurps autophagy, blocks senescence, and facilitates the proliferation of KSHV-infected cells.
authors.affiliation: Department of Microbiology and Immunology, Dalhousie University, 5850 College Street, Halifax, Nova Scotia B3H 4R2, Canada.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Leidal
authors.forename: David P
authors.initials: DP
authors.lastname: Cyr
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Hill
authors.forename: Patrick W K
authors.initials: PW
authors.lastname: Lee
authors.forename: Craig
authors.initials: C
authors.lastname: McCormick
mesh_terms: D000375:Aging; D001343:Autophagy; D004249:DNA Damage; D004260:DNA Repair; D019288:Herpesvirus 8, Human / Q000276:immunology / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D057131:Immune Evasion; D015513:Oncogene Proteins / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D015513:Oncogene Proteins; D014764:Viral Proteins; D037521:Virulence Factors