Resumen
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.
Idioma original | English |
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Páginas (desde-hasta) | 167-180 |
Número de páginas | 14 |
Publicación | Cell Host and Microbe |
Volumen | 11 |
N.º | 2 |
DOI | |
Estado | Published - feb. 16 2012 |
Nota bibliográfica
Funding Information:We thank Drs. Roy Duncan, Chris Richardson, John Rohde, and Rick Singer, as well as the members of the McCormick lab, for helpful discussions and critical manuscript review. We thank Drs. Don Ganem (UCSF), Robert Weinberg (MIT), William Hahn (Harvard), Terje Johansen (Tromsø), Gary Nolan (Stanford), Shou-Jiang Gao (UTHSC San Antonio), and Graham Dellaire (Dalhousie) for reagents. We thank Drs. Gary Faulkner and Don Stoltz for assistance with electron microscopy and Steven Whitefield for assistance with confocal microscopy. This work was supported by grants to C.M. and P.W.K.L. from the Canadian Institutes of Health Research (CIHR). D.P.C. is supported by a trainee award from The Beatrice Hunter Cancer Research Institute with funds provided by the Canadian Cancer Society, Nova Scotia Division.
ASJC Scopus Subject Areas
- Parasitology
- Microbiology
- Virology