CHC22 clathrin membrane recruitment uses SNX5 in bipartite interaction with secretory tether p115

The two clathrin isoforms, CHC17 and CHC22, mediate separate intracellular transport routes. CHC17 performs endocytosis and housekeeping membrane traffic in all cells. CHC22, expressed most highly in skeletal muscle, transports the glucose transporter GLUT4 from the endoplasmic-reticulum-to-Golgi intermediate compartment (ERGIC) directly to an intracellular GLUT4 storage compartment (GSC) from where GLUT4 can be mobilized to the plasma membrane by insulin. Here, the molecular determinants distinguishing CHC22 from CHC17 trafficking are defined. The C-terminal trimerization domain of CHC22 binds SNX5, which also binds the ERGIC tether p115. SNX5, and the functionally redundant SNX6, are required for CHC22 localization independently of their participation in the endosomal ESCPE-1 complex. In tandem, an isoform-specific patch in the CHC22 N-terminal domain separately mediates binding to p115. This dual mode of clathrin recruitment, involving interactions at both heavy chain termini, is required for CHC22 targeting to ERGIC membranes to mediate the Golgi bypass route for GLUT4 traffic. Interference with either interaction inhibits GLUT4 targeting to the GSC, defining a bipartite mechanism regulating a key pathway in human glucose metabolism.