G Alpha 13 Mediates Human Cytomegalovirus-Encoded Chemokine Receptor Us28-Induced Cell Death In Melanoma

US28, a constitutively active G-protein-coupled receptor encoded by the human cytomegalovirus, leads to mechanistically unknown programmed cell death. Here we show that expression of wild-type US28 in human melanoma cells leads to apoptotic cell death via caspase 3 activation along with reduced cell proliferation. Reduced tumor growth upon US28 expression was observed in a xenograft mouse model. The signaling mute US28R129A showed a reduced antiproliferative effect. On evaluating different G-proteins coupled to US28 for signal transduction, G13 was identified as the main G-protein executing the apoptotic effect. Silencing of G13 but not Gq resulted in a substantial increase in cell survival. Overexpression of G13 but not Gq and their GTPase deficient forms G13Q226L and GqQ209L, respectively, confirmed the requirement of G13 for US28 mediated cell death. Increasing expression of G13 alone induced cell death underscoring its relay function for US28 mediated decreased cell viability. Further reduced expression of G13 in melanoma cell lines isolated from advanced lesions and melanoma tissue was observed. These findings identified G13 as crucial for US28-induced cell death, substantiating that the effect of US28 on cell fate depends on preferred G-protein binding.What's new? Human cytomegalovirus (HCMV) can influence oncogenic processes, an ability that may stem from the activities of HMCV-encoded proteins. The HCMV-encoded G-protein-coupled receptor US28, for example, promotes tumorigenesis via disturbance of signaling pathways. But US28 also can induce cell death, an alternate effect explored in the present study. In human melanoma cells, the apoptosis-inducing properties of US28 were discovered to be mediated through the G-protein subunit G13. Differences in G13 expression in melanoma cells and tissue governed susceptibility to US28 apoptosis induction. The results suggest that G13 availability dictates the US28 cell death-inducing effect.