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Sci. Signal., 3 August 2010
Vol. 3, Issue 133, p. ra58
[DOI: 10.1126/scisignal.2001180]
RESEARCH ARTICLES
HCMV-Encoded Chemokine Receptor US28 Mediates Proliferative Signaling Through the IL-6–STAT3 Axis
Erik Slinger1,
David Maussang1,
Andreas Schreiber1,
Marco Siderius1,
Afsar Rahbar2,
Alberto Fraile-Ramos3,4,
Sergio A. Lira5,
Cecilia Söderberg-Nauclér2, and
Martine J. Smit1*
1 Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, the Netherlands. 2 Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital Solna and Karolinska Institutet, 171 76 Stockholm, Sweden. 3 Department of Molecular and Cell Biology, Centro Nacional de Biotecnologia, Consejo Superior de Investigaciones Cientificas, Campus Universidad Autonoma de Madrid, 28006 Madrid, Spain. 4 MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK. 5 Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
Abstract:
US28 is a viral G protein (heterotrimeric guanosine triphosphate–binding protein)–coupled receptor encoded by the human cytomegalovirus (HCMV). In addition to binding and internalizing chemokines, US28 constitutively activates signaling pathways linked to cell proliferation. Here, we show increased concentrations of vascular endothelial growth factor and interleukin-6 (IL-6) in supernatants of US28-expressing NIH 3T3 cells. Increased IL-6 was associated with increased activation of the signal transducer and activator of transcription 3 (STAT3) through upstream activation of the Janus-activated kinase JAK1. We used conditioned growth medium, IL-6–neutralizing antibodies, an inhibitor of the IL-6 receptor, and short hairpin RNA targeting IL-6 to show that US28 activates the IL-6–JAK1–STAT3 signaling axis through activation of the transcription factor nuclear factor B and the consequent production of IL-6. Treatment of cells with a specific inhibitor of STAT3 inhibited US28-dependent [3H]thymidine incorporation and foci formation, suggesting a key role for STAT3 in the US28-mediated proliferative phenotype. US28 also elicited STAT3 activation and IL-6 secretion in HCMV-infected cells. Analyses of tumor specimens from glioblastoma patients demonstrated colocalization of US28 and phosphorylated STAT3 in the vascular niche of these tumors. Moreover, increased phospho-STAT3 abundance correlated with poor patient outcome. We propose that US28 induces proliferation in HCMV-infected tumors by establishing a positive feedback loop through activation of the IL-6–STAT3 signaling axis.
* To whom correspondence should be addressed. E-mail: mj.smit{at}few.vu.nl
Citation: E. Slinger, D. Maussang, A. Schreiber, M. Siderius, A. Rahbar, A. Fraile-Ramos, S. A. Lira, C. Söderberg-Nauclér, M. J. Smit, HCMV-Encoded Chemokine Receptor US28 Mediates Proliferative Signaling Through the IL-6–STAT3 Axis. Sci. Signal.3, ra58 (2010).
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B and the consequent production of IL-6. Treatment of cells with a specific inhibitor of STAT3 inhibited US28-dependent [3H]thymidine incorporation and foci formation, suggesting a key role for STAT3 in the US28-mediated proliferative phenotype. US28 also elicited STAT3 activation and IL-6 secretion in HCMV-infected cells. Analyses of tumor specimens from glioblastoma patients demonstrated colocalization of US28 and phosphorylated STAT3 in the vascular niche of these tumors. Moreover, increased phospho-STAT3 abundance correlated with poor patient outcome. We propose that US28 induces proliferation in HCMV-infected tumors by establishing a positive feedback loop through activation of the IL-6–STAT3 signaling axis.
