The largest superfamily of membrane proteins that translate extracellular signals into intracellular messages are the 7-transmembrane-spanning (7TM) G protein-coupled receptors (GPCR). One of the ways in which their activity is controlled is by the process of desensitization and endocytosis, whereby agonist-activated receptors are rapidly and often reversibly silenced through removal from the cell surface. Indeed, following endocytosis, individual receptors can be sorted differentially between recycling endosomes and lysosomes, which controls the reversibility of the silencing. Thus, endocytosis can either serve as a mechanism for receptor resensitization by delivering receptors back to the plasma membrane or facilitate receptor downregulation by serving as the first step towards targeting the receptors to lysosomes for degradation. The sorting of receptors to the lysosomal pathway can be facilitated by interaction with an array of accessory proteins. One of these proteins is the GPCR-associated sorting protein 1 (GASP-1), which specifically targets several 7TM-GPCR to the lysosomal pathway after endocytosis. Furthermore, GASP-1 was recently found to directly affect the signaling capacity of a 7TM-GPCR. Importantly, the in vivo relevance of GASP-1-dependent receptor sorting has also begun to be verified in animal models. Here, we summarize the recent advances in elucidating GASP-1-dependent receptor sorting functions and their potential implications in vivo.
† These authors contributed equally to this work.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 Gα q /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.
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.
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