Building GLUT4 Vesicles: CHC22 Clathrin’s Human Touch

Abstract

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. HighlightsInsulin 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 CHC22clathrin 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.

Run for your life: can exercise be used to effectively target GLUT4 in diabetic cardiac disease?

“…Under resting conditions, GLUT4 is sequestered intracellularly in specialised GLUT4 containing insulin responsive vesicles (IRVs; see Fig. 2 ) ( Gould, Brodsky & Bryant, 2020 ). Post-prandial elevations in blood glucose concentration are sensed and then responded to by the pancreas through increased release of insulin.…”

“…2 ). These effectors include the Myo1C motor protein that powers GLUT4 translocation, the exocyst complex that tethers IRVs at the PM and the SNARE proteins that facilitate the fusion of these opposing membranes ( Gould, Brodsky & Bryant, 2020 ). GLUT4 is unique in this mode of regulation.…”

“…GLUT4 is essential in matching glucose supply and demand in the tissues where it is needed most, and, therefore, also in the regulation of circulating blood glucose levels. The critical role of this protein is underscored by findings that muscular insulin sensitivity is strongly correlated to GLUT4 protein content ( Kraegen et al, 1993 ), impaired insulin stimulated GLUT4 PM trafficking in the skeletal muscle of T2D is the primary defect defining this disease ( Garvey et al, 1998 ; Gould, Brodsky & Bryant, 2020 ) and that GLUT4 protein overexpression preserves systemic insulin sensitivity in a commonly employed mouse model of diabetes ( Atkinson et al, 2013 ).…”

Regulatory effects of protein S-acylation on insulin secretion and insulin action

“…IRAP S-acylation occurs on two cysteines at the cytosol membrane interface of this type II membrane proteins [125]. IRAP is proposed to play a role as both cargo and a regulator of the formation of the GSC/IRVs [98,126]. In part, this role is mediated by the formation of a complex between IRAP, p115 and CHC22 clathrin which is thought to control a 'Golgi bypass' route for GLUT4 trafficking which is particularly well-developed in human cells [105].…”

EFR3 and phosphatidylinositol 4-kinase IIIα regulate insulin-stimulated glucose transport and GLUT4 dispersal in 3T3-L1 adipocytes

“…This is mediated by the regulated delivery of the glucose transporter GLUT4 from intracellular stores to the plasma membrane (PM). A wealth of information has underpinned our understanding of intracellular GLUT4 trafficking and the mechanism by which GLUT4-containing vesicles fuse with the PM (Gould et al, 2020;Jaldin-Fincati et al, 2017;Klip et al, 2019;Saltiel, 2021;Santoro et al, 2021).…”