Sortilin and retromer mediate retrograde transport of Glut4 in 3T3-L1 adipocytes

Pan, Xiang; Zaarur, Nava; Singh, Maneet; Morin, Peter J.; Kandror, Konstantin V.

doi:10.1091/mbc.e16-11-0777

Cited by 71 publications

(72 citation statements)

References 47 publications

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“…Is the recycling of cargo through the retriever pathway, as shown for LDLR in the liver, similar in fat? The interesting data on the role of the WASH complex on GLUT2 trafficking opens up the possibility of a potential function of the retriever‐CCC‐WASH complex on GLUT4 in vivo, as has been suggested from adipocyte cell lines . Also, is the control of signaling through the endosomal system comparable between muscle and liver?…”

Section: Discussionmentioning

confidence: 88%

Metabolic regulation through the endosomal system

Gilleron

Gerdes

Zeigerer

2019

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The endosomal system plays an essential role in cell homeostasis by controlling cellular signaling, nutrient sensing, cell polarity and cell migration. However, its place in the regulation of tissue, organ and whole body physiology is less well understood. Recent studies have revealed an important role for the endosomal system in regulating glucose and lipid homeostasis, with implications for metabolic disorders such as type 2 diabetes, hypercholesterolemia and non‐alcoholic fatty liver disease. By taking insights from in vitro studies of endocytosis and exploring their effects on metabolism, we can begin to connect the fields of endosomal transport and metabolic homeostasis. In this review, we explore current understanding of how the endosomal system influences the systemic regulation of glucose and lipid metabolism in mice and humans. We highlight exciting new insights that help translate findings from single cells to a wider physiological level and open up new directions for endosomal research.

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Section: Discussionmentioning

confidence: 88%

Metabolic regulation through the endosomal system

Gilleron

Gerdes

Zeigerer

2019

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“…Remarkably, Usp25m, but not Usp25a, catalyzed TUG cleavage in cotransfection experiments. This effect of transfected Usp25m was enhanced by coexpression of sortilin, another protein induced during adipocyte differentiation, which is essential for the formation of GSVs (5,28,34,35). It is formally possible that Usp25m acts on another upstream target involved in GSV budding.…”

Section: Usp25m Regulates Insulin Action In Adipocytesmentioning

confidence: 99%

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

Habtemichael

Don

Alcázar-Román

et al. 2018

Journal of Biological Chemistry

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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 (ether containing a BX domain forLUT4) 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 biquitin-ike). 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.

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“…The large intracellular loop has also been implicated in intracellular sorting (51). The trafficking machinery that interacts with these different motifs is poorly defined, although roles for the GGA, retromer, and AP1 adaptor complexes have been proposed (52)(53)(54)(55). The core molecular machinery required for GSV formation remains to be identified.…”

Section: The Glut4 Itinerary and Its Many Unknownsmentioning

confidence: 99%

Thirty sweet years of GLUT4

Klip

McGraw

James

2019

Journal of Biological Chemistry

262

260

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A pivotal metabolic function of insulin is the stimulation of glucose uptake into muscle and adipose tissues. The discovery of the insulin-responsive glucose transporter type 4 (GLUT4) protein in 1988 inspired its molecular cloning in the following year. It also spurred numerous cellular mechanistic studies laying the foundations for how insulin regulates glucose uptake by muscle and fat cells. Here, we reflect on the importance of the GLUT4 discovery and chronicle additional key findings made in the past 30 years. That exocytosis of a multispanning membrane protein regulates cellular glucose transport illuminated a novel adaptation of the secretory pathway, which is to transiently modulate the protein composition of the cellular plasma membrane. GLUT4 controls glucose transport into fat and muscle tissues in response to insulin and also into muscle during exercise. Thus, investigation of regulated GLUT4 trafficking provides a major means by which to map the essential signaling components that transmit the effects of insulin and exercise. Manipulation of the expression of GLUT4 or GLUT4-regulating molecules in mice has revealed the impact of glucose uptake on whole-body metabolism. Remaining gaps in our understanding of GLUT4 function and regulation are highlighted here, along with opportunities for future discoveries and for the development of therapeutic approaches to manage metabolic disease.

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Sortilin and retromer mediate retrograde transport of Glut4 in 3T3-L1 adipocytes

Abstract: Sortilin is involved in the anterograde traffic of lysosomal enzymes and substrates. It also transports Glut4 in the opposite, retrograde, direction in a retromer-dependent fashion.

Cited by 71 publications

References 47 publications

Metabolic regulation through the endosomal system

Metabolic regulation through the endosomal system

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

Thirty sweet years of GLUT4

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