The Role Of AMPK-TBC1D17-Rab5 Signaling In Resulatins GLUT4 Translocation

Type Ⅱ diabetes,characterized by insulin resistance,has seriously affected human health.The translocation of glucose transporter 4(GLUT4)regulates the absorption of glucose in skeletal muscle and adipose tissue,which is crucial to maintaining blood glucose homeostasis.Rab5 is a kind of small GTPase protein belonging to the Ras superfamily,whose activity is negatively regulated by GTPase activating protein(GAP).Previous studies showed that Rab5 is responsible for the formation,transportation and fusion of intracellular vesicles.Recent studies have shown that Rab5 also participates in the process of GLUT4 translocation.However,the upstream regulator of Rab5 in this process is still unknown,and the detailed physiological role of Rab5 deserves more investigation.Our previous study showed that Rab5a plays a crucial role in modulating injury-induced skeletal muscle regeneration.Here,we uncover a new physiological function of Rab5a in maintaining blood glucose homeostasis.Firstly,we find that Rab5a mKO mice not only have significant weight gain,but also have reduced glucose tolerance and insulin resistance,as well as hyperinsulinemia.These results suggest a disfunction of glucose metabolism due to Rab5a deficiency.Mechanism studies show that overexpressing GDP-locked Rab5a mutant(S34N)inhibits the translocation of GLUT4 in myoblast C2C12 cells;On the contrary,activating AMPK can increase the activity of Rab5a,thus promoting the translocation of GLUT4 by AICAR treatment(an agonist of AMPK)or glucose deprivation in myoblasts.Furthermore,with the spectrum screening analysis and GST-R5BD pull-down assay,we discover that TBC1D17 functions as a GTPase activating protein(GAP)towards Rab5a.Furthermore,AMPK directly phosphorylates TBC1D17 at the site of Serl68.And the phosphorylation of TBC1D17 down regulates its GAP effect towards Rab5a,which promotes the translocation of GLUT4 from GSV(GLUT4 storage vesicles)to plasma membrane.These above results showe that the AMPK-TBC1D17-Rab5a signaling can regulate the translocation of GLUT4 in insulin independent manner,which provides a potential target for the treatment of type-Ⅱ diabetes mellitus.