CHC22 Clathrin Diverts GLUT4 from the ER-to-Golgi Intermediate Compartment for Intracellular Sequestration

The Glucose Transporter 4 (GLUT4) in muscle and adipose tissue mediates post-prandial blood glucose clearance by insulin-stimulated GLUT4 translocation to the cell surface from an intracellular GLUT4 storage compartment (GSC). Deregulation of this process establishes insulin resistance and contributes to pathogenesis of type-2 diabetes (T2D). Endocytic pathways targeting GLUT4 to the GSC after insulin-mediated release have been defined extensively in rodent models. Here we map the biosynthetic trafficking pathway leading to initial GSC formation, which is less characterised, and differs between humans and rodents. In human muscle and adipocytes, GSC formation involves the non-canonical isoform of clathrin, CHC22, which does not mediate endocytosis and accumulates at sites of GLUT4 sequestration during insulin resistance. Mice have lost the CLTCL1 gene encoding CHC22, and use conventional CHC17 clathrin for GSC formation by endocytic pathways that do not replace CHC22 function in human GSC formation. Here we report that CHC22 controls GLUT4 transport from the ER-to-Golgi intermediate compartment (ERGIC) in an unconventional secretory pathway, bypassing the Golgi, to form the human GSC. This specialized route for human GLUT4 membrane traffic has relevance for understanding insulin resistance.