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G?13 mediates human cytomegalovirus-encoded chemokine receptor US28-induced cell death in melanoma.

ABSTRACT: 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, G?13 was identified as the main G-protein executing the apoptotic effect. Silencing of G?13 but not G?q resulted in a substantial increase in cell survival. Overexpression of G?13 but not G?q and their GTPase deficient forms G?13Q226L and G?qQ209L, respectively, confirmed the requirement of G?13 for US28 mediated cell death. Increasing expression of G?13 alone induced cell death underscoring its relay function for US28 mediated decreased cell viability. Further reduced expression of G?13 in melanoma cell lines isolated from advanced lesions and melanoma tissue was observed. These findings identified G?13 as crucial for US28-induced cell death, substantiating that the effect of US28 on cell fate depends on preferred G-protein binding.

SUBMITTER: Joshi S

PROVIDER: S-EPMC4496263 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Gα13 mediates human cytomegalovirus-encoded chemokine receptor US28-induced cell death in melanoma.

Joshi Shripad S Wels Christian C Beham-Schmid Christine C Fukunaga-Kalabis Mizuho M Holmen Sheri L SL Otte Marcus M Herlyn Meenhard M Waldhoer Maria M Schaider Helmut H

International journal of cancer 20150316 6

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-pro ...[more]

PMID: 25754407

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Project description:Human cytomegalovirus (HCMV) is a beta-herpesvirus carried by ∼80% of the world's population. Acute infections are asymptomatic in healthy individuals but generate diverse syndromes in neonates, solid organ transplant recipients, and HIV-infected individuals. The HCMV gene US28 encodes a homolog of a human chemokine receptor that is able to bind several chemokines and HIV gp120. Deep sequencing technologies were used to sequence US28 directly from 60 clinical samples from Indonesian HIV patients and Australian renal transplant recipients, healthy adults, and neonates. Molecular modeling approaches were used to predict whether nine nonsynonymous mutations in US28 may alter protein binding to a panel of six chemokines and two variants of HIV gp120. Ninety-two percent of samples contained more than one variant of HCMV, as defined by at least one nonsynonymous mutation. Carriage of these variants differed between neonates and adults, Australian and Indonesian samples, and saliva samples and blood leukocytes. Two nonsynonymous mutations (N170D and R267K) were associated with increased levels of immediate early protein 1 (IE-1) and glycoprotein B (gB) HCMV-reactive antibodies, suggesting a higher viral burden. Seven of the nine mutations were predicted to alter binding of at least one ligand. Overall, HCMV variants are common in all populations and have the potential to affect US28 interactions with human chemokines and/or gp120 and alter responses to the virus. The findings relied on deep sequencing technologies applied directly to clinical samples, so the variants exist in vivo. IMPORTANCE Human cytomegalovirus (HCMV) is a common viral pathogen of solid organ transplant recipients, neonates, and HIV-infected individuals. HCMV encodes homologs of several host genes with the potential to influence viral persistence and/or pathogenesis. Here, we present deep sequencing of an HCMV chemokine receptor homolog, US28, acquired directly from clinical specimens. Carriage of these variants differed between patient groups and was associated with different levels of circulating HCMV-reactive antibodies. These features are consistent with a role for US28 in HCMV persistence and pathogenesis. This was supported by in silico analyses of the variant sequences demonstrating altered ligand-binding profiles. The data delineate a novel approach to understanding the pathogenesis of HCMV and may impact the development of an effective vaccine.

Dataset Information

G?13 mediates human cytomegalovirus-encoded chemokine receptor US28-induced cell death in melanoma.

Publications

Gα13 mediates human cytomegalovirus-encoded chemokine receptor US28-induced cell death in melanoma.

Similar Datasets

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