Jonathan Bogan, MD
Research & Publications
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 proteins that sequester GLUT4 in nonendosomal, intracellular vesicles in the absence of insulin. Insulin then acts on these proteins 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 site-specific endoproteolytic cleavage of TUG to liberate these vesicles for translocation to the cell surface. GLUT4 and other vesicle cargoes 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 cargoes are re-sequestered. This arrangement obviates the need for ongoing TUG cleavage during sustained insulin exposure. TUG cleavage generates an N-terminal product that functions as a novel ubiquitin-like protein modifier, implicating new enzymatic activities in insulin action. In mice, this proteolytic pathway controls whole-body and muscle-specific glucose uptake, and data show that vesicle cargoes other than GLUT4 contribute to the regulation of vasopressin action and, possibly, lipid metabolism. In addition, the TUG C-terminal product enters the nucleus and regulates gene expression to control fatty acid oxidation, thermogenesis, and overall energy expenditure. 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 and obesity.
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.
Arginine Vasopressin; Cell Biology; Diabetes Mellitus, Type 2; Endocrinology; Glucose; Metabolic Diseases; Ubiquitins; Protein Transport; Thermogenesis; Glucose Transporter Type 4
- Ubiquitin-like processing of TUG proteins as a mechanism to regulate glucose uptake and energy metabolism in fat and muscleBogan JS. Ubiquitin-like processing of TUG proteins as a mechanism to regulate glucose uptake and energy metabolism in fat and muscle Frontiers In Endocrinology 2022, 13: 1019405. PMID: 36246906, PMCID: PMC9556833, DOI: 10.3389/fendo.2022.1019405.
- Inhibitors of RNA and protein synthesis cause Glut4 translocation and increase glucose uptake in adipocytesMeriin AB, Zaarur N, Bogan JS, Kandror KV. Inhibitors of RNA and protein synthesis cause Glut4 translocation and increase glucose uptake in adipocytes Scientific Reports 2022, 12: 15640. PMID: 36123369, PMCID: PMC9485115, DOI: 10.1038/s41598-022-19534-5.
- Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptakeHabtemichael 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 secretionBogan JS. Granular detail of β cell structures for insulin secretion Journal Of Cell Biology 2021, 220: e202012082. PMID: 33427875, PMCID: PMC7802365, DOI: 10.1083/jcb.202012082.
- Vasopressin inactivation: Role of insulin-regulated aminopeptidaseLi DT, Habtemichael EN, Bogan JS. Vasopressin inactivation: Role of insulin-regulated aminopeptidase 2019, 113: 101-128. PMID: 32138946, DOI: 10.1016/bs.vh.2019.08.017.
- Acylation – A New Means to Control Traffic Through the GolgiErnst 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 adipocytesHabtemichael 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 Journal Of Biological Chemistry 2018, 293: 10466-10486. PMID: 29773651, PMCID: PMC6036200, DOI: 10.1074/jbc.ra118.003021.
- 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* Journal Of Biological Chemistry 2015, 290: 14454-14461. PMID: 25944897, PMCID: PMC4505512, DOI: 10.1074/jbc.c115.639203.
- 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* Journal Of Biological Chemistry 2015, 290: 4447-4463. PMID: 25561724, PMCID: PMC4326849, DOI: 10.1074/jbc.m114.603977.
- 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* Journal Of Biological Chemistry 2012, 287: 23932-23947. PMID: 22610098, PMCID: PMC3390669, DOI: 10.1074/jbc.m112.339457.
- Regulation of Glucose Transporter Translocation in Health and DiabetesBogan JS. Regulation of Glucose Transporter Translocation in Health and Diabetes Annual Review Of Biochemistry 2012, 81: 507-532. PMID: 22482906, DOI: 10.1146/annurev-biochem-060109-094246.
- 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* Journal Of Biological Chemistry 2011, 287: 6679-6692. PMID: 22207755, PMCID: PMC3307297, DOI: 10.1074/jbc.m111.284232.
- Dual-mode of insulin action controls GLUT4 vesicle exocytosisXu Y, Rubin BR, Orme CM, Karpikov A, Yu C, Bogan JS, Toomre DK. Dual-mode of insulin action controls GLUT4 vesicle exocytosis Journal Of Cell Biology 2011, 193: 643-653. PMID: 21555461, PMCID: PMC3166865, DOI: 10.1083/jcb.201008135.