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Open Access

The sorting protein GASP-1 regulates the constitutive signaling capacity of the virally encoded chemokine receptor US28

  • Pia Tschische1,
  • Elisabeth Moser1,
  • Dawn Thompson2,
  • Wolfgang Platzer1,
  • Henry Vischer3,
  • Martine J Smit3,
  • Helmut Schaider4,
  • Lene Martini2,
  • Jennifer Whistler2 and
  • Maria Waldhoer1Email author
BMC Pharmacology20099(Suppl 2):A4

https://doi.org/10.1186/1471-2210-9-S2-A4

Published: 12 November 2009

Background

Human cytomegalovirus (HCMV) is a widespread pathogen that has been shown to be present in various malignancies and it is also thought to be linked to vascular diseases. HCMV encodes the seven transmembrane (7 TM)/G protein-coupled receptor (GPCR) US28, which constitutively activates the Gαq/phospholipase C (PLC) pathway and downstream transcription factors such as the nuclear factor-κB (NF-κB) or the cyclic AMP responsive element binding protein (CREB). In this study we set out to elucidate the role of the GPCR-associated sorting protein-1 (GASP-1) in the regulation of the constitutive signaling capacity of US28.

Methods

To elucidate the role of GASP-1 in the regulation of the constitutive signaling capacity of US28 we disrupted the US28/GASP-1 interaction by either overexpression of dominant negative cGASP-1 or shRNA knock-down of endogenous GASP-1. To monitor the US28-mediated signaling we conducted inositol phosphate (IP) accumulation assays as well as luciferase reporter gene assays to check the activation of the transcription factors NF-κB and CREB.

Results

We find that GASP-1 is indeed able to modulate the signaling activity of US28. Disruption of the GASP-1/US28 interaction by either i) overexpression of dominant negative cGASP-1 or by ii) shRNA knock-down of endogenous GASP-1 alters the US28-mediated Gαq/PLC/IP accumulation as well as the activation of the transcription factors NF-κB and CREB.

Conclusion

By identifying the sorting protein GASP-1 as a key regulator of the constitutive signaling activity of US28, we may be one step closer to gaining a better understanding of this viral receptor and its significance in the pathogenesis implicated by HCMV.

Authors’ Affiliations

(1)
Institute of Experimental and Clinical Pharmacology, Medical University of Graz
(2)
Ernest Gallo Clinic and Research Center, University of California
(3)
Leiden/Amsterdam Center for Drug Research (LACDR), Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam
(4)
Department of Dermatology, Medical University of Graz

Copyright

© Tschische et al; licensee BioMed Central Ltd. 2009

This article is published under license to BioMed Central Ltd.

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