Glioblastoma Multiforme (GBM) is the most aggressive type of brain cancer. The human cytomegalovirus is detected in most GBM patient samples and encodes US28, a viral chemokine G protein-coupled receptor (GPCR). The constitutive activation (agonist-independent) of Gαq by US28 induces oncomodulatory properties such as cell inflammation, proliferation, and angiogenesis. Using bioluminescence resonance energy transfer (BRET)-based biosensors, we show that US28 constitutively activates all the Gα protein isoforms tested, but most importantly Gαq. Unlike typical viral GPCRs which are found in the plasma membrane, US28 is mainly localised in endosomes due to chronic internalisation. This poor expression at the plasma membrane is somehow surprising given the high constitutive activity of US28. However, since the last decade many GPCRs have been reported to activate Gα proteins from intracellular compartments such as endosomes upon GPCR internalisation. Using enhanced bystander BRET-based biosensors, we show a gradual redistribution of Gα proteins, in particular Gαq, from the plasma membrane to early, fast-recycling and slow-recycling endosomes concomitant with a gradual increase of Gαq constitutive activity when US28 is progressively overexpressed. These results suggest that the important US28 endosomal pool may be actively stimulating Gαq and the oncomodulatory signalling. Consequently, directly targeting a US28 blocker to the endosomes may represent a promising therapeutic approach to successfully block GBM malignancy.
|Publication status||Published - 26 Sep 2019|
|Event||Annual Research Symposium from the Centre of Membrane Proteins and Receptors - Nottingham, United Kingdom|
Duration: 26 Sep 2019 → …
|Conference||Annual Research Symposium from the Centre of Membrane Proteins and Receptors|
|Period||26/09/2019 → …|