A proteolytic pathway that controls glucose uptake in fat and muscle

Abstract

Insulin regulates glucose uptake by controlling the subcellular location of GLUT4 glucose transporters. GLUT4 is sequestered within fat and muscle cells during low-insulin states, and is translocated to the cell surface upon insulin stimulation. The TUG protein is a functional tether that sequesters GLUT4 at the Golgi matrix. To stimulate glucose uptake, insulin triggers TUG endoproteolytic cleavage. Cleavage accounts for a large proportion of the acute effect of insulin to mobilize GLUT4 to the cell surface. During ongoing insulin exposure, endocytosed GLUT4 recycles to the plasma membrane directly from endosomes, and bypasses a TUG-regulated trafficking step. Insulin acts through the TC10α GTPase and its effector protein, PIST, to stimulate TUG cleavage. This action is coordinated with insulin signals through AS160/Tbc1D4 and Tbc1D1 to modulate Rab GTPases, and with other signals to direct overall GLUT4 targeting. Data support the idea that the N-terminal TUG cleavage product, TUGUL, functions as a novel ubiquitin-like protein modifier to facilitate GLUT4 movement to the cell surface. The C-terminal TUG cleavage product is extracted from the Golgi matrix, which vacates an “anchoring” site to permit subsequent cycles of GLUT4 retention and release. Together, GLUT4 vesicle translocation and TUG cleavage may coordinate glucose uptake with physiologic effects of other proteins present in the GLUT4-containing vesicles, and with potential additional effects of the TUG C-terminal product. Understanding this TUG pathway for GLUT4 retention and release will shed light on the regulation of glucose uptake and the pathogenesis of type 2 diabetes.

Acetylation of TUG Protein Promotes the Accumulation of GLUT4 Glucose Transporters in an Insulin-responsive Intracellular Compartment

“…Recent data show that SIRT2 binds Akt and facilitates Akt phosphorylation (72). However, the increased insulin sensitivity we observed in vivo in intraperitoneal glucose tolerance tests of SIRT2 KO mice, compared with WT controls, is consistent with previous results showing that insulin action on TUG is independent of Akt (12,14,16,17). Thus, the data support a model in which SIRT2 knock-out mice have increased TUG acetylation, which facilitates trapping of GLUT4 in an insulinresponsive pool and which increases insulin sensitivity.…”

“…A second issue is that GLUT4 is distributed among multiple intracellular compartments and to two different exocytic pathways arising from GSVs and endosomes (12,13). The small size of GSVs makes these vesicles difficult to detect using total internal reflection fluorescence microscopy, so that endosome-derived GLUT4 may be taken for that present in GSVs (14). Altogether, the nature and regulation of GSVs continues to be debated.…”

“…Insulin then liberates GSVs by triggering site-specific endoproteolytic cleavage of TUG, which separates regions that bind GLUT4 from regions that bind Golgi proteins (17,18). Data imply that this action accounts for a substantial portion of the acute effect of insulin in fat and muscle (14). During ongoing insulin exposure, GLUT4 and other GSV cargos recycle to the cell surface from endosomes and bypass a TUG-regulated compartment (12).…”

“…Insulin signals acutely through the TC10␣ GTPase and its effector, PIST, to stimulate TUG cleavage (17,18). This signal may be transient, and it is coordinated with signals through Akt2 to AS160/Tbc1D4 and Tbc1D1 (1,14). These proteins modulate Rab GTPases to direct GSV trafficking and to return endocytosed GLUT4 to the cell surface directly from endosomes during ongoing stimulation (12,13).…”

Elmo2 Is a Regulator of Insulin-dependent Glut4 Membrane Translocation

“…to the lysosome), which leads to Glut4 degradation because the Elmo protein has been implicated in endosome trafficking (29). Alternatively, Elmo2 might affect the proteolytic pathway that controls Glut4 membrane trafficking to affect Glut4 expression because the proteolytic pathway plays a critical role in the Glut4 membrane trafficking in both adipocytes and muscle cells (30), an issue that requires further investigation.…”