The G-protein coupled receptor associated sorting protein GASP-1 regulates the signalling and trafficking of the viral chemokine receptor US28

Pia Tschische, Elisabeth Moser, Dawn Thompson, Henry F. Vischer, Gerald P. Parzmair, Veronika Pommer, Wolfgang Platzer, Thomas Schwarzbraun, Helmut Schaider, Martine J. Smit, Lene Martini, Jennifer Whistler, Maria Waldhoer

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Human cytomegalovirus (HCMV) encodes the seven transmembrane (7TM)/G-protein coupled receptor (GPCR) US28, which signals and endocytoses in a constitutive, ligand-independent manner. Here we show that, following endocytosis, US28 is targeted to the lysosomes for degradation as a consequence of its interaction with the GPCR-associated sorting protein-1 (GASP-1). We find that GASP-1 binds to US28 in vitro and that 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 is sufficient to inhibit the lysosomal targeting of US28 and slow its post-endocytic degradation. Furthermore, we found that GASP-1 affects US28-mediated signalling. The knock-down of endogenous GASP-1 impairs the US28-mediated Gαq/PLC/inositol phosphate (IP) accumulation as well as the activation of the transcription factors Nuclear Factor-κB (NF-κB) and cyclic AMP responsive element binding protein (CREB). Overexpression of GASP-1 enhances both IP accumulation and transcription factor activity. Thus, GASP-1 is an important cellular determinant that not only regulates the post-endocytic trafficking of US28, but also regulates the signalling capacities of US28.

Original languageEnglish (US)
Pages (from-to)660-674
Number of pages15
JournalTraffic
Volume11
Issue number5
DOIs
StatePublished - May 1 2010
Externally publishedYes

Keywords

  • Chemokine
  • Cytomegalovirus
  • G-protein coupled receptor
  • GASP-1
  • Post-endocytic sorting
  • Signalling
  • US28

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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  • Cite this

    Tschische, P., Moser, E., Thompson, D., Vischer, H. F., Parzmair, G. P., Pommer, V., Platzer, W., Schwarzbraun, T., Schaider, H., Smit, M. J., Martini, L., Whistler, J., & Waldhoer, M. (2010). The G-protein coupled receptor associated sorting protein GASP-1 regulates the signalling and trafficking of the viral chemokine receptor US28. Traffic, 11(5), 660-674. https://doi.org/10.1111/j.1600-0854.2010.01045.x