Insulin sends SEC16A packing

After a meal, insulin lowers blood glucose levels by stimulating the sugar's uptake into muscle and fat cells via the glucose transporter GLUT4. Insulin promotes GLUT4's translocation to the cell surface, a process that goes awry in patients with type II diabetes and which depends, in part, on the small GTPase RAB10. Bruno and Brumfield et al. reveal that RAB10 works with SEC16A—a protein involved in COPII vesicle biogenesis—to form the specialized transport vesicles that ferry GLUT4 to the plasma membrane (1). Under basal conditions, only a small amount of GLUT4 is present at the surface of adipocytes, whereas the majority of the protein localizes to a perinuclear recycling endosome/trans-Golgi network compartment. Insulin both slows GLUT4's internalization from the plasma membrane and enhances the transporter's delivery to the cell surface in GLUT4-specialized vesicles (GSVs), thereby increasing GLUT4 surface levels and glucose uptake (2). GLUT4's delivery to the plasma membrane is partially inhibited in the absence of RAB10 (3), but exactly how this small GTPase promotes the trans-porter's translocation remains unclear. Timothy McGraw and colleagues at Weill Cornell Medical College in New York wanted to identify the proteins that act downstream of RAB10. " Identifying RAB10's effec-tors would bring us one step closer to a molecular description of the pathway, " McGraw explains. McGraw and colleagues, led by Joanne Bruno and Alexandria Brumfi eld, took a biochemical approach to the problem, using mass spectrometry to identify proteins from insulin-stimulated adipocytes that bound to the active, GTP-bound form of RAB10 (1). One such interacting protein was SEC16A, and depleting this protein inhibited insulin-stimulated GLUT4 translocation to the same extent as knocking down RAB10. In addition, knocking down SEC16A prevented active RAB10 from stimulating GLUT4 translocation, indicating that the protein acts downstream of the GTPase. SEC16A nucleates the formation of COPII vesicles at ER exit sites (4), raising the possibility that RAB10 and SEC16A regulate GLUT4 translocation by controlling ER-to-Golgi transport. However, though knocking down the COPII coat protein SEC23A also impaired GLUT4 translocation, depleting other COPII components had no effect on the transporter's exocy-tosis. Moreover, RAB10 depletion had no effect on ER-to-Golgi traffi cking. " So it seems that there are two pools of SEC16A, " McGraw says. " One involved in ER exit and one—regulated by RAB10—that controls GLUT4 traffi cking. " Accordingly, a portion of SEC16A localized next to GLUT4 in the perinu-clear region of adipocytes. Proximity ligation assays revealed …