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Jonathan Bogan, MD

Associate Professor of Medicine (Endocrinology) and of Cell Biology

Contact Information

Jonathan Bogan, MD

Office Location

Mailing Address

  • Endocrinology

    PO Box 208020, 333 Cedar Street

    New Haven, CT 06520-8020

    United States

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Yale Medicine

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Research Summary

Dr. Bogan’s research seeks to understand how glucose uptake is regulated in muscle and fat cells. In these cell types, insulin causes glucose transporters to move from internal membranes to the cell surface. Glucose is then transported into the cells, and is removed from the bloodstream. The regulation of this process is defective in insulin-resistant states such as type 2 diabetes. Dr. Bogan’s laboratory identified regulated proteolytic cleavage as a novel biochemical mechanism to control glucose transporter movement and glucose uptake. Current efforts are focused on characterizing this mechanism in detail, and on determining how this pathway controls metabolism and physiology.

Specialized Terms: Protein trafficking; Ubiquitin-like modification; Cell structure; Insulin signaling; Type 2 diabetes; Metabolic diseases

Extensive Research Description

Dr. Bogan’s laboratory studies molecular mechanisms controlling GLUT4 glucose transporter targeting in adipose and muscle cells. In cell types, insulin stimulates glucose uptake by translocating GLUT4 from intracellular membranes to the cell surface. Understanding how this occurs has been a longstanding puzzle. Dr. Bogan and his coworkers identified a protein complex that sequesters GLUT4 in nonendosomal, intracellular vesicles in the absence of insulin. Insulin then acts on this complex to mobilize GLUT4 to the cell surface. This action is coordinated with other insulin signals that act on GTPases to direct vesicle targeting. Current work is directed to understand the biochemical mechanisms involved in this response, including phosphorylation, GTPase signaling, and ubiquitin-like modification pathways.

Much current work in the laboratory focuses on a proteolytic mechanism that regulates glucose uptake in fat and muscle. Previous work identified the TUG protein as a critical regulator of GLUT4 targeting, which limits cell-surface GLUT4 and glucose uptake in cells not stimulated with insulin. TUG traps GLUT4 in non-endosomal vesicles, bound at the Golgi matrix, and insulin triggers endoproteolytic cleavage of TUG to liberate these vesicles for translocation to the cell surface. GLUT4 and other vesicle cargos are then maintained at the cell surface by cycling through endosomes, and they bypass a TUG-regulated compartment until insulin signaling is terminated, and the cargos are re-sequestered. This arrangement obviates the need for ongoing TUG cleavage during sustained insulin exposure. TUG cleavage generates a product that functions as a novel ubiquitin-like protein modifier, implicating new enzymatic activities in insulin action. In mice, this proteolytic pathway controls glucose metabolism and energy expenditure, and data show that vesicle cargos other than GLUT4 contribute to the regulation of vasopressin action and, possibly, lipid metabolism. Thus, regulated TUG cleavage and vesicle translocation coordinates distinct physiologic outputs, and dysregulation of this pathway may contribute to multiple aspects of the metabolic syndrome.

The pathway that is utilized by GLUT4 is likely one instance of a general pathway to regulate the cell surface targeting of membrane proteins in response to extracellular stimuli. Work on GLUT4 targeting may thus have far-reaching implications for a wide range of physiology. In addition, this regulated pathway is likely a cell type-specific adaptation of a fundamental trafficking pathway present in most cells. Current work will elucidate this pathway and how it is adapted to control GLUT4, using a combination of biochemical and cell biological approaches, genetically engineered mice, and studies of organism-level metabolism and physiology.

Coauthors

Research Interests

Arginine Vasopressin; Cell Biology; Diabetes Mellitus, Type 2; Endocrinology; Glucose; Metabolic Diseases; Ubiquitins; Protein Transport; Thermogenesis; Glucose Transporter Type 4

Selected Publications

  • Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake.Habtemichael EN, Li DT, Camporez JP, Westergaard XO, Sales CI, Liu X, López-Giráldez F, DeVries SG, Li H, Ruiz DM, Wang KY, Sayal BS, González Zapata S, Dann P, Brown SN, Hirabara S, Vatner DF, Goedeke L, Philbrick W, Shulman GI, Bogan JS. Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake. Nature Metabolism 2021, 3: 378-393. PMID: 33686286, PMCID: PMC7990718, DOI: 10.1038/s42255-021-00359-x.
  • Granular detail of β cell structures for insulin secretion.Bogan JS. Granular detail of β cell structures for insulin secretion. The Journal Of Cell Biology 2021, 220 PMID: 33427875, PMCID: PMC7802365, DOI: 10.1083/jcb.202012082.
  • Vasopressin inactivation: Role of insulin-regulated aminopeptidase.Li DT, Habtemichael EN, Bogan JS. Vasopressin inactivation: Role of insulin-regulated aminopeptidase. Vitamins And Hormones 2020, 113: 101-128. PMID: 32138946, DOI: 10.1016/bs.vh.2019.08.017.
  • A Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance.Lyu K, Zhang Y, Zhang D, Kahn M, Ter Horst KW, Rodrigues MRS, Gaspar RC, Hirabara SM, Luukkonen PK, Lee S, Bhanot S, Rinehart J, Blume N, Rasch MG, Serlie MJ, Bogan JS, Cline GW, Samuel VT, Shulman GI. A Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance. Cell Metabolism 2020, 32: 654-664.e5. PMID: 32882164, PMCID: PMC7544641, DOI: 10.1016/j.cmet.2020.08.001.
  • Acylation - A New Means to Control Traffic Through the Golgi.Ernst AM, Toomre D, Bogan JS. Acylation - A New Means to Control Traffic Through the Golgi. Frontiers In Cell And Developmental Biology 2019, 7: 109. PMID: 31245373, PMCID: PMC6582194, DOI: 10.3389/fcell.2019.00109.
  • Usp25m protease regulates ubiquitin-like processing of TUG proteins to control GLUT4 glucose transporter translocation in adipocytes.Habtemichael EN, Li DT, Alcázar-Román A, Westergaard XO, Li M, Petersen MC, Li H, DeVries SG, Li E, Julca-Zevallos O, Wolenski JS, Bogan JS. Usp25m protease regulates ubiquitin-like processing of TUG proteins to control GLUT4 glucose transporter translocation in adipocytes. The Journal Of Biological Chemistry 2018, 293: 10466-10486. PMID: 29773651, PMCID: PMC6036200, DOI: 10.1074/jbc.RA118.003021.
  • Acetylation of TUG protein promotes the accumulation of GLUT4 glucose transporters in an insulin-responsive intracellular compartment.Belman JP, Bian RR, Habtemichael EN, Li DT, Jurczak MJ, Alcázar-Román A, McNally LJ, Shulman GI, Bogan JS. Acetylation of TUG protein promotes the accumulation of GLUT4 glucose transporters in an insulin-responsive intracellular compartment. The Journal Of Biological Chemistry 2015, 290: 4447-63. PMID: 25561724, PMCID: PMC4326849, DOI: 10.1074/jbc.M114.603977.
  • Coordinated Regulation of Vasopressin Inactivation and Glucose Uptake by Action of TUG Protein in Muscle.Habtemichael EN, Alcázar-Román A, Rubin BR, Grossi LR, Belman JP, Julca O, Löffler MG, Li H, Chi NW, Samuel VT, Bogan JS. Coordinated Regulation of Vasopressin Inactivation and Glucose Uptake by Action of TUG Protein in Muscle. The Journal Of Biological Chemistry 2015, 290: 14454-61. PMID: 25944897, PMCID: PMC4505512, DOI: 10.1074/jbc.C115.639203.
  • Enhanced fasting glucose turnover in mice with disrupted action of TUG protein in skeletal muscle.Löffler MG, Birkenfeld AL, Philbrick KM, Belman JP, Habtemichael EN, Booth CJ, Castorena CM, Choi CS, Jornayvaz FR, Gassaway BM, Lee HY, Cartee GD, Philbrick W, Shulman GI, Samuel VT, Bogan JS. Enhanced fasting glucose turnover in mice with disrupted action of TUG protein in skeletal muscle. The Journal Of Biological Chemistry 2013, 288: 20135-50. PMID: 23744065, PMCID: PMC3711282, DOI: 10.1074/jbc.M113.458075.
  • Regulation of glucose transporter translocation in health and diabetes.Bogan JS. Regulation of glucose transporter translocation in health and diabetes. Annual Review Of Biochemistry 2012, 81: 507-32. PMID: 22482906, DOI: 10.1146/annurev-biochem-060109-094246.
  • Endoproteolytic cleavage of TUG protein regulates GLUT4 glucose transporter translocation.Bogan JS, Rubin BR, Yu C, Löffler MG, Orme CM, Belman JP, McNally LJ, Hao M, Cresswell JA. Endoproteolytic cleavage of TUG protein regulates GLUT4 glucose transporter translocation. The Journal Of Biological Chemistry 2012, 287: 23932-47. PMID: 22610098, PMCID: PMC3390669, DOI: 10.1074/jbc.M112.339457.
  • The ubiquitin regulatory X (UBX) domain-containing protein TUG regulates the p97 ATPase and resides at the endoplasmic reticulum-golgi intermediate compartment.Orme CM, Bogan JS. The ubiquitin regulatory X (UBX) domain-containing protein TUG regulates the p97 ATPase and resides at the endoplasmic reticulum-golgi intermediate compartment. The Journal Of Biological Chemistry 2012, 287: 6679-92. PMID: 22207755, PMCID: PMC3307297, DOI: 10.1074/jbc.M111.284232.
  • Dual-mode of insulin action controls GLUT4 vesicle exocytosis.Xu Y, Rubin BR, Orme CM, Karpikov A, Yu C, Bogan JS, Toomre DK. Dual-mode of insulin action controls GLUT4 vesicle exocytosis. The Journal Of Cell Biology 2011, 193: 643-53. PMID: 21555461, PMCID: PMC3166865, DOI: 10.1083/jcb.201008135.
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