The York Research Database

Glucose Transporter 4 (GLUT4) is sequestered inside muscle and fat, then releasedby vesicle traffic to the cell surface in response to post-prandial insulin for bloodglucose clearance. Here we map the biogenesis of this GLUT4 traffic pathway inhumans, which involves clathrin isoform CHC22. We observe that GLUT4 transitsthrough the early secretory pathway more slowly than the constitutively-secretedGLUT1 transporter and localize CHC22 to the endoplasmic-reticulum-to-Golgiintermediatecompartment (ERGIC). CHC22 functions in transport from the ERGIC,as demonstrated by an essential role in forming the replication vacuole of Legionellapneumophila bacteria, which requires ERGIC-derived membrane. CHC22 complexeswith ERGIC tether p115, GLUT4 and sortilin and down-regulation of either p115 orCHC22, but not GM130 or sortilin abrogate insulin-responsive GLUT4 release. Thisindicates CHC22 traffic initiates human GLUT4 sequestration from the ERGIC, anddefines a role for CHC22 in addition to retrograde sorting of GLUT4 after endocyticrecapture, enhancing pathways for GLUT4 sequestration in humans relative to mice,which lack CHC22.