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 L Whistler, Maria Waldhoer

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

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 Galphaq/PLC/inositol phosphate (IP) accumulation as well as the activation of the transcription factors Nuclear Factor-kappaB (NF-kappaB) 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
Pages (from-to)660-74
Number of pages15
JournalTraffic
Volume11
Issue number5
DOIs
Publication statusPublished - May 2010

Keywords

  • Chemokines
  • Cyclic AMP Response Element-Binding Protein
  • Cytomegalovirus
  • Endocytosis
  • Humans
  • Inositol Phosphates
  • Ligands
  • NF-kappa B
  • Proteins
  • Receptors, Chemokine
  • Receptors, G-Protein-Coupled
  • Signal Transduction
  • Type C Phospholipases

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