| dc.description.abstract | Glucose transporters are principal gatekeepers of cellular glucose metabolism. Understanding mechanisms that regulate their activity, trafficking, and degradation can provide insight into physiological regulation of glucose homeostasis and diseases that arise from dysregulation of glucose transport. Glucose is known to stimulate endocytic clearance of the human glucose transporter GLUT1, but once internalized the mechanisms that regulate its trafficking itineraries are not well understood. Here, we report that increased glucose availability triggers lysosomal trafficking of GLUT1 in HeLa cells, with a subpopulation of GLUT1 routed through ESCRT-associated late endosomal compartments. This itinerary requires the arrestin-like protein TXNIP, which interacts with both clathrin and E3 ubiquitin ligases to promote GLUT1 lysosomal trafficking. We also find that glucose stimulates GLUT1 ubiquitylation, which in turn promotes GLUT1 lysosomal trafficking. Our results suggest excess glucose first stimulates TXNIP-mediated endocytosis of GLUT1 and, subsequently, ubiquitylation to promote trafficking to the lysosome. Our findings underscore how complex coordination of multiple regulators is required for fine tuning of GLUT1 stability at the cell surface. | |
