Ubiquitin-like processing of TUG proteins as a mechanism to regulate glucose uptake and energy metabolism in fat and muscle

Abstract

In response to insulin stimulation, fat and muscle cells mobilize GLUT4 glucose transporters to the cell surface to enhance glucose uptake. Ubiquitin-like processing of TUG (Aspscr1, UBXD9) proteins is a central mechanism to regulate this process. Here, recent advances in this area are reviewed. The data support a model in which intact TUG traps insulin-responsive “GLUT4 storage vesicles” at the Golgi matrix by binding vesicle cargoes with its N-terminus and matrix proteins with its C-terminus. Insulin stimulation liberates these vesicles by triggering endoproteolytic cleavage of TUG, mediated by the Usp25m protease. Cleavage occurs in fat and muscle cells, but not in fibroblasts or other cell types. Proteolytic processing of intact TUG generates TUGUL, a ubiquitin-like protein modifier, as the N-terminal cleavage product. In adipocytes, TUGUL modifies a single protein, the KIF5B kinesin motor, which carries GLUT4 and other vesicle cargoes to the cell surface. In muscle, this or another motor may be modified. After cleavage of intact TUG, the TUG C-terminal product is extracted from the Golgi matrix by the p97 (VCP) ATPase. In both muscle and fat, this cleavage product enters the nucleus, binds PPARγ and PGC-1α, and regulates gene expression to promote fatty acid oxidation and thermogenesis. The stability of the TUG C-terminal product is regulated by an Ate1 arginyltransferase-dependent N-degron pathway, which may create a feedback mechanism to control oxidative metabolism. Although it is now clear that TUG processing coordinates glucose uptake with other aspects of physiology and metabolism, many questions remain about how this pathway is regulated and how it is altered in metabolic disease in humans.

UBXN9 governs GLUT4-mediated spatial confinement of RIG-I-like receptors and signaling

“…These results are consistent with previously published datasets reporting heightened interferon pathways in myopathic skeletal muscle 47 , 51 , 52 . Unexpectedly, SLC2A4 (encoding GLUT4), and several genes involved in GLUT4 trafficking 16 , were downregulated in DM muscle relative to controls ( Fig. 7c , Supplemental Fig.…”

“…The magnitude of GLUT4 mobilization is directly proportional to the total UBXN9-GLUT4 complexes that are dissociated during insulin treatment 16 . The results in Fig.…”

“…The above findings suggest that trafficking of GLUT4 to the plasma membrane suppresses RLR signaling by repositioning RIG-I away from MAVS. Mobilization of GSVs involves the vesicular trafficking machinery as well as numerous accessory proteins in close association with GLUT4 16 , 40 . Considering other protein(s) of anterograde transport could be responsible for RLR tethering, we first examined the interaction between GLUT4 and RLRs under the same conditions known to promote GLUT4 translocation ( Figs.…”

“…GLUT4 is the predominant, insulin/muscle contraction-regulated glucose transporter in adipose, skeletal, and cardiac muscle tissues, and is essential for the maintenance of whole-body glucose homeostasis 16 . In the basal state, GLUT4 is primarily sequestered within intracellular GLUT4 storage vesicles (GSVs), which are tethered to the Golgi matrix by a direct interaction with the Golgi-associated ubiquitin regulatory X (UBX) domain-containing protein UBXN9 (also known as TUG) 17 , 18 .…”