CHC22 clathrin initiates biogenesis of the human GLUT4 storage compartment from the early secretory pathway

Post-prandial blood glucose is cleared by insulin-mediated release of Glucose Transporter 4 (GLUT4) from an intracellular GLUT4 storage compartment (GSC) to the surface of muscle and adipose tissue. Here we map the biosynthetic pathway for human GSC formation, which involves the clathrin isoform CHC22. We observe that GLUT4 transits more slowly through the early secretory pathway than the constitutively secreted GLUT1 transporter, and show CHC22 colocalizes with p115 in the endoplasmic-reticulum-to-Golgi-intermediate compartment (ERGIC). We find CHC22 mediates membrane traffic from the early secretory pathway during formation of Legionella pneumophila9s replication vacuole, which also acquires components of the GLUT4 pathway. We show that p115 but not GM130 is required for GSC formation from the ERGIC, indicating Golgi bypass. This GSC biogenesis pathway is attenuated in mice, which lack CHC22 and rely mainly on recapture of surface GLUT4 to populate their GSC. In humans, GLUT4 traffic to the GSC is enhanced by CHC22 at the ERGIC, which has implications for pathways to insulin resistance.