Endoproteolytic Cleavage of TUG Protein Regulates GLUT4 Glucose Transporter Translocation

Bogan, Jonathan; Rubin, Bradley R.; Yu, Chenfei; Löffler, Michael; Orme, Charisse M.; Belman, Jonathan P.; McNally, Leah; Hao, Mingming; Cresswell, James

doi:10.1074/jbc.m112.339457

Cited by 47 publications

(129 citation statements)

References 96 publications

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“…This general membrane trafficking pathway is adapted in a cell type-specific manner in which TUG undergoes insulin-stimulated endoproteolytic cleavage to control GLUT4 translocation (11,15). In mice, global disruption of the gene encoding TUG may cause embryonic lethality, and no conditional knock-out model is presently available.…”

Section: Resultsmentioning

confidence: 99%

“…No insulin was infused, and care was taken to minimize the increase in plasma glucose, which would stimulate secretion of endogenous insulin. Blood samples were drawn by tail vein at 2,5,15,25,35,45, and 55 min after the initiation of this 2-deoxy-D-glucose (2DOG) infusion. At study completion, mice were anesthetized with an intravenous pentobarbital sodium injection (150 mg/kg).…”

Section: Methodsmentioning

confidence: 99%

“…Quantification of individual proteins was done using a LI-COR Odyssey imaging system. Antibodies used for immunoblotting include polyclonal antibodies directed to the C termini of TUG and GLUT4 (11,12,15). Monoclonal antibody 6H directed to the N terminus of the Na ϩ ,K ϩ -ATPase ␣1 subunit was a gift from Dr. Michael Caplan (39).…”

Section: Methodsmentioning

confidence: 99%

“…Data from 3T3-L1 adipocytes show that this mechanism is a major site of insulin action to regulate GLUT4 trafficking and glucose uptake (12,13). TUG resides at the cis side of the Golgi complex and links GLUT4-containing vesicles to Golgi matrix proteins present at this location (14,15). Insulin signals through the TC10␣ GTPase and its effector, PIST, to stimulate TUG endoproteolytic cleavage, which liberates the vesicles and is required for highly insulin-responsive GLUT4 translocation and glucose uptake (15).…”

mentioning

confidence: 99%

“…TUG resides at the cis side of the Golgi complex and links GLUT4-containing vesicles to Golgi matrix proteins present at this location (14,15). Insulin signals through the TC10␣ GTPase and its effector, PIST, to stimulate TUG endoproteolytic cleavage, which liberates the vesicles and is required for highly insulin-responsive GLUT4 translocation and glucose uptake (15). This pathway is coordinated with insulin signals through Akt2 to AS160/Tbc1D4 and (in muscle) Tbc1D1, which modulate specific Rab GTPases, as well as with signals to promote vesicle fusion at the plasma membrane (16 -22).…”

mentioning

confidence: 99%

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

Löffler¹,

Birkenfeld²,

Philbrick³

et al. 2013

Journal of Biological Chemistry

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Background: Insulin stimulates endoproteolytic cleavage of TUG proteins to promote glucose uptake in cultured adipocytes, but the role of this pathway in muscle is uncharacterized. Results: Transgenic mice with constitutive and unregulated TUG cleavage in muscle had increased whole-body and musclespecific glucose uptake during fasting. Conclusion: Insulin acts through TUG to control glucose uptake in muscle. Significance: Understanding insulin action will elucidate diabetes pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Löffler¹,

Birkenfeld²,

Philbrick³

et al. 2013

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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Pancreatic Hormones

Norman

2015

Hormones

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Endoproteolytic Cleavage of TUG Protein Regulates GLUT4 Glucose Transporter Translocation

Cited by 47 publications

References 96 publications

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

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

A proteolytic pathway that controls glucose uptake in fat and muscle

Pancreatic Hormones

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