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

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.

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Correspondence to Maria Waldhoer.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Tschische, P., Moser, E., Thompson, D. et al. The sorting protein GASP-1 regulates the constitutive signaling capacity of the virally encoded chemokine receptor US28. BMC Pharmacol 9 (Suppl 2), A4 (2009). https://doi.org/10.1186/1471-2210-9-S2-A4

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

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