Vasopressin inactivation: Role of insulin-regulated aminopeptidase

Don, LI; Habtemichael, Estifanos N.; Bogan, Jonathan S.

doi:10.1016/bs.vh.2019.08.017

Cited by 11 publications

(17 citation statements)

References 136 publications

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“…Altered targeting of GSV proteins may occur in parallel to attenuated Akt signaling, and may account for insulin resistance not attributable to attenuated Akt signaling 4 . Of note, altered targeting of IRAP proteins during fasting may alter vasopressin dynamics to contribute to hypertension in the setting of insulin resistance 14 , 30 . The data presented here suggest that these alterations may also reduce energy expenditure, since the generation and subsequent action of the TUG C-terminal product is decreased.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to GLUT4, GSVs contain IRAP, which inactivates circulating vasopressin, and LRP1 and sortilin, which bind lipoproteins 5 , 30 . Transgenic mice with constitutive TUG cleavage in muscle exhibit not only increased fasting muscle glucose uptake, due to increased GLUT4 at the plasma membrane, but also increased water intake, due to increased IRAP at the plasma membrane and accelerated vasopressin degradation 14 .…”

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confidence: 99%

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Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake

et al. 2021

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Mechanisms to coordinately regulate energy expenditure and glucose uptake into muscle and fat cells are not well described. Insulin stimulates glucose uptake in part by causing site-specific endoproteolytic cleavage of TUG, which mobilizes GLUT4 glucose transporters to the cell surface. Here, we show that the TUG C-terminal cleavage product enters the nucleus, binds the transcriptional regulators PGC-1a and PPARg, and increases oxidative metabolism and thermogenic protein expression. Muscle-specific genetic manipulation of this pathway impacts whole-body energy expenditure, independent of glucose uptake. The PPARg2 Pro12Ala polymorphism, which reduces diabetes risk, enhances TUG binding. The TUG cleavage product stabilizes PGC-1a and is itself susceptible to an Ate1 arginyltransferase -dependent degradation mechanism; binding of the TUG product confers Ate1-dependent stability upon PGC-1a. We conclude that TUG cleavage coordinates energy expenditure with glucose uptake, that this pathway may contribute to the thermic effect of food, and that its attenuation may be important in obesity..

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake

et al. 2021

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“…This causes accelerated degradation of circulating vasopressin, an IRAP substrate, and may enhance blood flow in muscles that have increased metabolic activity ( 13 , 22 ). Possibly, altered targeting of IRAP contributes to hypertension in insulin-resistant individuals ( 2 ). Other GSV cargoes, such as LRP1 and sortilin, bind to ApoE and ApoA5, and we speculate that targeting of these proteins regulates lipid metabolism ( 2 , 27 , 49 ).…”

Section: Glut4 Storage Vesicles Are Regulated By Tug Proteinsmentioning

confidence: 99%

“…In both cell types, the insulin-stimulated increase in glucose transport is pivotal to this regulation ( 1 ). Remarkably, the same molecular processes that increase glucose transport may also enhance glucose delivery ( 2 ). Yet, the physiologic regulation of these processes, and how they are affected in insulin resistance, is not well understood.…”

Section: Introductionmentioning

confidence: 99%

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

Bogan

2022

Front. Endocrinol.

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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.

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“…In addition, it has been shown to be involved in several other functions, ranging from the insulin metabolic pathway to vesicular trafficking and even in cognitive processes (7,8). Furthermore, the three genes have been found associated with autoimmune and inflammatory conditions, hypertension, and cancer (2,(9)(10)(11)(12)(13)(14)(15). Since they are regulators of the Renin-Angiotensin system (RAS), their imbalance can have indeed consequences on different aspects of the associated pathologies (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

A short ERAP2 that binds IRAP is expressed in macrophages independently from gene variation

Mattorre

Caristi

Donato

et al. 2022

Preprint

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The M1 zinc metalloproteases ERAP1, ERAP2 and IRAP play a role in HLA-I antigen presentation by refining the peptidome either in the ER (ERAP1 and ERAP2) or in the endosomes (IRAP). They have been also entrusted with other, although less defined, functions such as the regulation of the angiotensin system and blood pressure. In humans, ERAP1 and IRAP are commonly expressed. ERAP2 instead has evolved under balancing selection that maintains two haplotypes one of which undergoing RNA splicing leading to nonsense-mediated decay and loss of protein. Hence, likewise in rodents in which the ERAP2 gene is missing, about a quarter of the human population does not express ERAP2. We report here that macrophages, but not monocytes or other mononuclear blood cells, express and secrete an ERAP2 shorter form independently from the haplotype. The generation of this short ERAP2 is due to an autocatalytic cleavage within a distinctive structural motif and requires an acidic microenvironment. Remarkably, this short ERAP2 binds IRAP and the two molecules are co-expressed in the endosomes as well as in the cell membrane. Of note, the same phenomenon could be observed in some cancer cells. These data prompt to reconsider the role of ERAP2 which might have been maintained in humans because fulfilling a relevant function as short form in specialized cells.

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Vasopressin inactivation: Role of insulin-regulated aminopeptidase

Cited by 11 publications

References 136 publications

Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake

Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake

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

A short ERAP2 that binds IRAP is expressed in macrophages independently from gene variation

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