Usp25m protease regulates ubiquitin-like processing of TUG proteins to control GLUT4 glucose transporter translocation in adipocytes

Insulin stimulates the exocytic translocation of specialized vesicles in adipocytes, which inserts GLUT4 glucose transporters into the plasma membrane to enhance glucose uptake. Previous results support a model in which TUG (Tether containing a UBX domain for GLUT4) proteins trap these GLUT4 storage...

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Bibliographic Details
Published in:The Journal of biological chemistry 2018-07, Vol.293 (27), p.10466-10486
Main Authors: Habtemichael, Estifanos N., Li, Don T., Alcázar-Román, Abel, Westergaard, Xavier O., Li, Muyi, Petersen, Max C., Li, Hanbing, DeVries, Stephen G., Li, Eric, Julca-Zevallos, Omar, Wolenski, Joseph S., Bogan, Jonathan S.
Format: Article
Language:English
Subjects:
adipocyte
Adipocytes - cytology
Adipocytes - drug effects
Adipocytes - metabolism
Animals
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cell Biology
Cell Membrane - metabolism
Cells, Cultured
Glucose - metabolism
glucose transporter type 4 (GLUT4)
Glucose Transporter Type 4 - genetics
Glucose Transporter Type 4 - metabolism
Hypoglycemic Agents - pharmacology
insulin
Insulin - pharmacology
insulin resistance
Intracellular Signaling Peptides and Proteins
kinesin
Kinesin - genetics
Kinesin - metabolism
Male
membrane trafficking
Mice
Mice, Inbred C57BL
Motor Activity
protein processing
protein translocation
Protein Transport
Proteolysis
Rats
Rats, Sprague-Dawley
Signal Transduction
Ubiquitin - metabolism
Ubiquitin Thiolesterase - genetics
Ubiquitin Thiolesterase - metabolism
ubiquitylation (ubiquitination)
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Summary:Insulin stimulates the exocytic translocation of specialized vesicles in adipocytes, which inserts GLUT4 glucose transporters into the plasma membrane to enhance glucose uptake. Previous results support a model in which TUG (Tether containing a UBX domain for GLUT4) proteins trap these GLUT4 storage vesicles at the Golgi matrix and in which insulin triggers endoproteolytic cleavage of TUG to translocate GLUT4. Here, we identify the muscle splice form of Usp25 (Usp25m) as a protease required for insulin-stimulated TUG cleavage and GLUT4 translocation in adipocytes. Usp25m is expressed in adipocytes, binds TUG and GLUT4, dissociates from TUG-bound vesicles after insulin addition, and colocalizes with TUG and insulin-responsive cargoes in unstimulated cells. Previous results show that TUG proteolysis generates the ubiquitin-like protein, TUGUL (for TUGubiquitin-like). We now show that TUGUL modifies the kinesin motor protein, KIF5B, and that TUG proteolysis is required to load GLUT4 onto these motors. Insulin stimulates TUG proteolytic processing independently of phosphatidylinositol 3-kinase. In nonadipocytes, TUG cleavage can be reconstituted by transfection of Usp25m, but not the related Usp25a isoform, together with other proteins present on GLUT4 vesicles. In rodents with diet-induced insulin resistance, TUG proteolysis and Usp25m protein abundance are reduced in adipose tissue. These effects occur soon after dietary manipulation, prior to the attenuation of insulin signaling to Akt. Together with previous data, these results support a model whereby insulin acts through Usp25m to mediate TUG cleavage, which liberates GLUT4 storage vesicles from the Golgi matrix and activates their microtubule-based movement to the plasma membrane. This TUG proteolytic pathway for insulin action is independent of Akt and is impaired by nutritional excess.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.RA118.003021