KSHV vGPCR: A VIRAL ONCOPROTEIN THAT TRIGGERS AUTOPHAGY AND CELLULAR SENESCENCE
Cyr, David P
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Autophagy (literally to ‘self-eat’) is an intracellular, catabolic mechanism to degrade and recycle cytoplasmic contents in response to metabolic, oxidative, and genotoxic stresses. Autophagy plays an important role in cellular homeostasis, and dysfunctional autophagic activity has been implicated in an array of human diseases. Importantly, autophagy has recently been identified to function in host defence against intracellular pathogens, including viruses. For this reason, many viruses have evolved strategies to subvert or exploit autophagy and block its antiviral effects. Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi’s sarcoma (KS), an AIDS-related cancer of the endothelium. KSHV gene products have evolved to support viral replication and evade immune surveillance. Some of these same gene products impact KS tumourigenesis, but the precise mechanisms have yet to be elucidated. Furthermore, the impact of autophagy on KSHV replication and KS tumourigenesis remains unexplored. The KSHV viral G-protein-coupled receptor (vGPCR) is a constitutively active signalling molecule that stimulates a number of host regulatory pathways that would be expected to impact autophagy, including PI3K/Akt/mTOR and JNK. Moreover, vGPCR is expressed during lytic replication when the antiviral autophagic response may threaten virion production. Here, vGPCR activity has been definitively shown to trigger autophagy in endothelial cells using immunoblot analysis, fluorescent reporter proteins, and transmission electron microscopy. Furthermore, preliminary data suggest that this stimulatory effect is evoked through JNK activation. Taken together, these findings indicate that vGPCR likely elicits autophagic responses during KSHV lytic replication. Recently, autophagy has been recognized as a molecular barrier to tumourigenesis, influencing cell survival, cell death, or a form of cell cycle arrest called oncogene-induced senescence (OIS). Remarkably, like many host oncogenes, ectopic expression of vGPCR triggers OIS in endothelial cells. This response is dependent on vGPCR signalling activity, as an inactive form of vGPCR (R143A) fails to trigger OIS. Furthermore, vGPCR OIS is atypical in that it does not involve DNA damage responses (DDRs). Together, these autophagic and senescence responses to ectopic vGPCR expression illustrate the potency of its oncogenic potential. The significance of vGPCR-induced autophagy and senescence during KSHV replication and KS development is presently unclear. I speculate that autophagy represents a hurdle that the virus must overcome in vivo. In my working model, potent vGPCR oncogenic signalling activity sets off the alarm, eliciting autophagic responses. It seems likely that additional lytic viral gene products may serve to undermine these autophagic responses and permit viral replication and dissemination in vivo.