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Abstract
Proteins involved in the spaciotemporal regulation of GLUT4 trafficking represent potential therapeutic targets for the treatment of insulin resistance and type 2 diabetes. A key regulator of insulin- and exercise-stimulated glucose uptake and GLUT4 trafficking is TBC1D1. This study aimed to identify proteins that regulate GLUT4 trafficking and homeostasis via TBC1D1. Using an unbiased quantitative proteomics approach, we identified proteins that interact with TBC1D1 in C2C12 myotubes including VPS13A and VPS13C, the Rab binding proteins EHBP1L1 and MICAL1, and the calcium pump SERCA1. These proteins associate with TBC1D1 via its phosphotyrosine binding (PTB) domains and their interactions with TBC1D1 were unaffected by AMPK activation, distinguishing them from the AMPK regulated interaction between TBC1D1 and AMPKα1 complexes. Depletion of VPS13A or VPS13C caused a post-transcriptional increase in cellular GLUT4 protein and enhanced cell surface GLUT4 levels in response to AMPK activation. The phenomenon was specific to GLUT4 because other recycling proteins were unaffected. Our results provide further support for a role of the TBC1D1 PTB domains as a scaffold for a range of Rab regulators, and also the VPS13 family of proteins which have been previously linked to fasting glycaemic traits and insulin resistance in genome wide association studies.
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Details
1 University of Bristol, School of Biochemistry, Biomedical Sciences Building, Bristol, UK (GRID:grid.5337.2) (ISNI:0000 0004 1936 7603)
2 Leibniz Center for Diabetes Research at Heinrich Heine University, Medical Faculty, Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany (GRID:grid.429051.b) (ISNI:0000 0004 0492 602X); German Center for Diabetes Research (DZD), München-Neuherberg, Germany (GRID:grid.452622.5)
3 Kagoshima University Graduate School of Medical and Dental Sciences, Department of Biochemistry and Genetics, Kagoshima, Japan (GRID:grid.258333.c) (ISNI:0000 0001 1167 1801)