Building GLUT4 Vesicles: CHC22 Clathrin's Human Touch.

Gwyn W Gould,Frances M Brodsky,Nia J Bryant

doi:10.1016/j.tcb.2020.05.007

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.

Highlights

Insulin stimulates glucose transport in fat and muscle cells by triggering the regulated delivery of GLUT4-containing insulin-responsive vesicles (IRVs) to the cell surface
We propose the idea of two distinct CHC22-containing complexes, one of CHC22/GGA2/sortilin/GLUT4 involved in retrograde sorting of GLUT4 to IRVs within endosomes, and another of CHC22/p115/insulin-responsive aminopeptidase (IRAP)/GLUT4 that mediates the sorting of newly synthesised GLUT4 from the endoplasmic reticulum–Golgi intermediate compartment (ERGIC) (Figure 3)
Many new questions arise: what are the relative contributions of these different routes into the GLUT4 storage compartment (GSC)/IRVs? Does the balance between them change under different physiological conditions and in different species? It is plausible that different physiological needs dictate this balance – might this be altered by exercise or prolonged high blood glucose? Glycosylation of GLUT4 is necessary for function [75] – begging the question of how GLUT4 moving from the ERGIC directly into IRVs acquires complex glycosylation modifications? What is the role of CHC22 itself – does it sequester GLUT4 cargo through specific adaptors?

Summary

Trends in Cell Biology

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). We discuss GLUT4 sorting in different species and how studies of CHC22 have identified new routes for GLUT4 trafficking. 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. The names used here and the meaning we ascribe to them are given below, together with some other abbreviations commonly used in the field: GSC

IRV GSV

Key Elements of Structure or Function

Key Figure

Findings

Outstanding Questions