Building GLUT4 Vesicles: CHC22 Clathrin’s Human Touch

Insulin stimulates glucose transport by triggering regulated delivery of intracellular vesicles containing the GLUT4 glucose transporter to the plasma membrane. This process is defective in diseases such as type 2 diabetes (T2DM). While studies in rodent cells have been invaluable in understanding GLUT4 traffic, evolutionary plasticity must be considered when extrapolating these findings to humans. Recent work has identified species-specific distinctions in GLUT4 traffic, notably the participation of a novel clathrin isoform, CHC22, in humans but not rodents. Here, we discuss GLUT4 sorting in different species and how studies of CHC22 have identified new routes for GLUT4 trafficking. We further consider how different sorting-protein complexes relate to these routes and discuss other implications of these pathways in cell biology and disease. Insulin stimulates glucose transport in fat and muscle cells by triggering the regulated delivery of GLUT4-containing IRVs to the cell surface.GLUT4 trafficking in human cells involves the noncanonical clathrin isoform CHC22 that sorts GLUT4 to the GSC.CHC22 clathrin is not expressed in rodents where different mechanisms underlie GLUT4 trafficking.New work has shown that CHC22-clathrin directs newly synthesised GLUT4 from the ER–Golgi intermediate compartment to the GSC without transit through the Golgi, in addition to mediating endosomal sorting of GLUT4.CHC22 clathrin interacts with p115, sortilin, IRAP, and GGA2 to mediate these distinct trafficking pathways.CHC22 clathrin enhances GLUT4 sequestration in human cells and is crucial for insulin-stimulated glucose transport.The newly identified CHC22-dependent pathway from the ERGIC could also operate in other cell types to control the delivery of cargo to specialised organelles.