Camus, S. M. | Search bioRxiv

bioRxiv2018

Evolution of the CLTCL1 Gene Encoding CHC22 Clathrin Reveals Selection Influencing CHC22’s Role in Human Glucose Metabolism

CHC22 clathrin plays a key role in intracellular membrane traffic of the insulin-responsive glucose transporter GLUT4 in humans. We performed population genetic and phylogenetic analyses of the CHC22-encoding CLTCL1 gene, revealing independent gene loss in at least two vertebrate lineages, after arising from gene duplication. All vertebrates retained the paralogous CLTC gene encoding CHC17 clathrin, which mediates endocytosis. For vertebrates retaining CLTCL1, strong evidence for purifying selection supports CHC22 functionality. All human populations maintained two high frequency CLTCL1 allelic variants, encoding either methionine or valine at position 1316. Functional studies indicated that CHC22-V1316, which is more frequent in farming populations than in hunter-gatherers, has different cellular dynamics than M1316-CHC22 and is less effective at controlling GLUT4 membrane traffic, attenuating its insulin-regulated response. These analyses suggest that ancestral human dietary change influenced selection of allotypes that affect CHC22s role in metabolism and have potential to differentially influence the human insulin response.

genetics↗

bioRxiv2018

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

Glucose Transporter 4 (GLUT4) is sequestered inside muscle and fat, then released by vesicle traffic to the cell surface in response to post-prandial insulin for blood glucose clearance. Here we map the biogenesis of this GLUT4 traffic pathway in humans, which involves clathrin isoform CHC22. We observe that GLUT4 transits through the early secretory pathway more slowly than the constitutively-secreted GLUT1 transporter and localize CHC22 to the endoplasmic-reticulum-to-Golgi-intermediate compartment (ERGIC). CHC22 functions in transport from the ERGIC, as demonstrated by an essential role in forming the replication vacuole of Legionella pneumophila bacteria, which requires ERGIC-derived membrane. CHC22 complexes with ERGIC tether p115, GLUT4 and sortilin and down-regulation of either p115 or CHC22, but not GM130 or sortilin abrogate insulin-responsive GLUT4 release. This indicates CHC22 traffic initiates human GLUT4 sequestration from the ERGIC, and defines a role for CHC22 in addition to retrograde sorting of GLUT4 after endocytic recapture, enhancing pathways for GLUT4 sequestration in humans relative to mice, which lack CHC22.\n\nSummaryBlood glucose clearance relies on insulin-mediated exocytosis of glucose transporter 4 (GLUT4) from sites of intracellular sequestration. We show that in humans, CHC22 clathrin mediates membrane traffic from the ER-to-Golgi Intermediate Compartment, which is needed for GLUT4 sequestration during GLUT4 pathway biogenesis.

cell biology↗