Enhanced Fasting Glucose Turnover in Mice with Disrupted Action of TUG Protein in Skeletal Muscle

Löffler, Michael; Birkenfeld, Andreas L.; Philbrick, Katerina M.; Belman, Jonathan P.; Habtemichael, Estifanos N.; Booth, Carmen J.; Castorena, Carlos M.; Choi, Cheol Soo; Jornayvaz, François R.; Gassaway, Brandon M.; Lee, Hui Young; Cartee, Gregory D.; Philbrick, William M.; Shulman, Gerald I.; Samuel, Varman T.; Bogan, Jonathan

doi:10.1074/jbc.m113.458075

Cited by 20 publications

(82 citation statements)

References 75 publications

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“…It is thus thought to trap GSVs intracellularly by linking them to the cis-Golgi matrix in unstimulated cells (17,19). 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).…”

Section: Together These Data Support a Model In Which Tug Acetylatiomentioning

confidence: 99%

“…Quadriceps muscles were excised, snap-frozen in liquid N 2 , and stored at Ϫ80°C. Tissues were homogenized in ice-cold radioimmune precipitation buffer using a Qiagen TissueLyser II, as described (18). Immunoblotting and densitometry was performed as above.…”

Section: Methodsmentioning

confidence: 99%

“…Blood samples were taken by tail bleeding at 0, 15, 30, 45, 60, 90, and 120 min after the injection and were used for measurement of glucose (using a YSI 2700D glucose analyzer, YSI Inc.) and insulin (using an ELISA, Millipore Inc.). Body composition analyses were performed using a Bruker Minispec analyzer, as described previously (18).…”

Section: Methodsmentioning

confidence: 99%

“…This explains how insulin causes a dose-dependent discharge of GSVs from a sequestered pool into a cell surface-recycling pathway (20). 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).…”

Section: Together These Data Support a Model In Which Tug Acetylatiomentioning

confidence: 99%

“…The TUG (tether containing a UBX domain for GLUT4) protein, encoded by the Aspscr1 gene, was proposed as the first molecular marker for GSVs and was proposed to regulate the basal intracellular retention and insulin-stimulated release of these vesicles (12,(15)(16)(17)(18). TUG binds GLUT4 through its N-terminal region and can simultaneously bind the Golgi proteins, PIST and Golgin-160, through its C-terminal region (17).…”

Section: Together These Data Support a Model In Which Tug Acetylatiomentioning

confidence: 99%

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

Belman

Bian²,

Habtemichael³

et al. 2015

Journal of Biological Chemistry

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Background: Insulin stimulates glucose uptake by triggering TUG proteolysis, which liberates intracellular storage vesicles containing GLUT4. Results: TUG acetylation modulates its interaction with Golgi matrix proteins and enhances its function to trap GLUT4 storage vesicles within unstimulated cells. SIRT2 modulates TUG acetylation and controls insulin sensitivity in vivo. Conclusion: TUG acetylation promotes GLUT4 accumulation in insulin-responsive vesicles. Significance: Nutritional status modulates insulin-stimulated glucose uptake.

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Section: Together These Data Support a Model In Which Tug Acetylatiomentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Together These Data Support a Model In Which Tug Acetylatiomentioning

confidence: 99%

Section: Together These Data Support a Model In Which Tug Acetylatiomentioning

confidence: 99%

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

Belman

Bian²,

Habtemichael³

et al. 2015

Journal of Biological Chemistry

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A proteolytic pathway that controls glucose uptake in fat and muscle

Belman

Habtemichael

Bogan

2013

Rev Endocr Metab Disord

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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.

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Cellular Regulation of Glucose Uptake by Glucose Transporter GLUT4

Govers

2014

Advances in Clinical Chemistry

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Enhanced Fasting Glucose Turnover in Mice with Disrupted Action of TUG Protein in Skeletal Muscle

Cited by 20 publications

References 75 publications

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

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

A proteolytic pathway that controls glucose uptake in fat and muscle

Cellular Regulation of Glucose Uptake by Glucose Transporter GLUT4

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