Ins (endocytosis) and outs (exocytosis) of GLUT4 trafficking

Abstract

Glucose transporter 4 (GLUT4) is the major insulin-regulated glucose transporter expressed mainly in muscle and adipose tissue. GLUT4 is stored in a poorly characterized intracellular vesicular compartment and translocates to the cell surface in response to insulin stimulation resulting in an increased glucose uptake. This process is essential for the maintenance of normal glucose homeostasis and involves a complex interplay of trafficking events and intracellular signaling cascades. Recent studies have identified sortilin as an essential element for the formation of GLUT4 storage vesicles during adipogenesis and Golgi-localized gamma-ear-containing Arf-binding protein (GGA) as a key coat adaptor for the entry of newly synthesized GLUT4 into the specialized compartment. Insulin-stimulated GLUT4 translocation from this compartment to the plasma membrane appears to require the Akt/protein kinase B substrate termed AS160 (Akt substrate of 160kDa). In addition, the VPS9 domain-containing protein Gapex-5 in complex with CIP4 appears to function as a Rab31 guanylnucleotide exchange factor that is necessary for insulin-stimulated GLUT4 translocation. Here, we attempt to summarize recent advances in GLUT4 vesicle biogenesis, intracellular trafficking and membrane fusion.

Figure 1. Insulin signaling pathway regulates GLUT4 intracellular trafficking

Newly synthesized GLUT4 traffic through a GGA-dependent and trans-Golgi Network (TGN) sorting into the insulin-responsive storage compartment (IRC). In the basal state, GLUT4 is mainly sequestered into the IRC and translocates to the plasma membrane (PM) after insulin stimulation. Exit from the IRC is prevented by AS160 that function to maintain a putative Rab in an inactive state (left). However, following insulin stimulation, AS160 is phosphorylated and inactivated by Akt-dependent phosphorylation (right). Several Rab proteins and effectors that have been implicated endocytosis (Rab4 and 5), recycling back and forth between endosome and TGN (Rabip4/Rab4, Rab11 and 14) are indicated.

Figure 2. GLUT4 vesicle docking, tethering and fusion

This schematic model shown that the docking of GLUT4 vesicles with the plasma membrane requires the Exocyst complex that is formed from the assembly of 8 distinct proteins. Insulin activates a small GTP binding protein TC10 that recruits Exo70 with Sec6 and Sec8 to lipid raft microdomains in the plasma membrane. The SNARE dependent fusion involves VAMP2, Syntaxin4 and SNAP23. Several syntaxin 4 binding partners have been identified including one member of the Munc18 family (Munc18c), Synip and Tomosyn. Munc18 proteins induces a closed conformational state of syntaxin thereby rendering it unable to bind to VAMP or SNAP. More over, insulin activation of PKC induces the formation of a complex with 80K-H and Munc18c to promote VAMP2 binding to syntaxin 4 that enhances GLUT4 fusion with the plasma membrane.