Brodsky, FM

Bryant, NJ

Camus, MD

Camus, SM

Esk, C

Figueras-Novoa, C

Gould, GW

Kioumourtzoglou, D

Mukherjee, S

Perez, F

English

UCL Discovery

Clathrin Heavy Chain 22 (CHC22) controls biogenesis of the human Glucose Transporter 4 (GLUT4) storage compartment (GSC) from the early secretory pathway.  Stéphane M. Camus1,2,3,4,10, Marine D. Camus1,2,3,4,10, Carmen Figueras-Novoa10, L. Amanda Sadacca10 Christopher Esk5, Gwyn W. Gould6, Dimitrios Kioumourtzoglou6,7, Franck Perez8,9, Nia J. Bryant7, Shaeri Mukherjee3,4* and Frances M. Brodsky1,2,3,4,10,*   1Department of Bioengineering and Therapeutic Sciences, 2Department of Pharmaceutical Chemistry, 3Department of Microbiology and Immunology, 4The G.W. Hooper Foundation, University of California San Francisco, San Francisco, CA 94143, USA 5IMBA Institute of Molecular Biotechnology GmbH, Vienna, Austria 6Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ. UK. 7Department of Biology, University of York, York, YO10 5DD. UK 8 Institut Curie, 26 rue d’Ulm, 75248 Paris Cedex 05, France. 9 CNRS UMR 144, 26 rue d’Ulm, 75248 Paris Cedex 05, France. 10 Present address: Division of Biosciences, University College London, London WC1E 6BT, UK *Co-corresponding authors   Aims: Intracellular GLUT4 trafficking to the GSC is critical for insulin-mediated GLUT4 translocation to the cell surface and glucose homeostasis, and its impairment contributes to pathogenesis of Type 2 diabetes. However, pathways leading to GSC biogenesis are unknown. We previously determined that formation of the perinuclear GSC relies on the non-canonical isoform of clathrin CHC22. In this work, we mapped the CHC22-mediated GLUT4 trafficking pathway leading to GSC biogenesis in humans. This will provide new insights into the pathophysiology of Type 2 diabetes and will foster novel therapeutic strategies. Methods: We combined super-resolution fluorescence microscopy and insulin-mediated GLUT4 translocation experiments quantified by FACS in HeLa-GLUT4 and human skeletal muscle cells expressing human GLUT4 tagged with exofacial Haemagglutinin and cytosolic GFP. We also took advantage of the Legionella pneumophila’s property to hijack its host’s early secretory trafficking machinery to probe for CHC22 function. Results: Super resolution microscopy located CHC22 at the ER-to-Golgi Intermediate Compartment. Functional experiments with L.p. confirmed that CHC22 was operating in the early secretory pathway, trafficking core components of the GLUT4 pathway: IRAP, sortilin and GGA2. We showed by co-immunoprecipitation that CHC22 interacts with p115 and siRNA experiments indicated that CHC22 and p115 co-operate to establish insulin sensitivity by trafficking GLUT4 to the GSC via a GM130-independent manner. Summary: Our data show that in humans, the formation of insulin sensitive GSC depends on a trafficking pathway where both CHC22 and p115 cooperate at the ERGIC to form GLUT4 vesicles and establish the GSC. 

Clathrin heavy chain 22 controls biogenesis of the human glucose transporter 4 storage compartment from the early secretory pathway

https://discovery.ucl.ac.uk/id/eprint/10072075/3/Camus_2018Oct17-Diabetes%20UK-abstract.pdf

Clathrin heavy chain 22 controls biogenesis of the human glucose transporter 4 storage compartment from the early secretory pathway

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UCL Discovery