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Science 324 (5931): 1192-1196

Copyright © 2009 by the American Association for the Advancement of Science

A Role for the CHC22 Clathrin Heavy-Chain Isoform in Human Glucose Metabolism

Stéphane Vassilopoulos,1,2,3,4,* Christopher Esk,1,2,3,4,* Sachiko Hoshino,1,2,3,4,*,{dagger} Birgit H. Funke,5,{ddagger} Chih-Ying Chen,1,2,3,4 Alex M. Plocik,5,§ Woodring E. Wright,6 Raju Kucherlapati,5,7 Frances M. Brodsky1,2,3,4,||

Abstract: Intracellular trafficking of the glucose transporter GLUT4 from storage compartments to the plasma membrane is triggered in muscle and fat during the body’s response to insulin. Clathrin is involved in intracellular trafficking, and in humans, the clathrin heavy-chain isoform CHC22 is highly expressed in skeletal muscle. We found a role for CHC22 in the formation of insulin-responsive GLUT4 compartments in human muscle and adipocytes. CHC22 also associated with expanded GLUT4 compartments in muscle from type 2 diabetic patients. Tissue-specific introduction of CHC22 in mice, which have only a pseudogene for this protein, caused aberrant localization of GLUT4 transport pathway components in their muscle, as well as features of diabetes. Thus, CHC22-dependent membrane trafficking constitutes a species-restricted pathway in human muscle and fat with potential implications for type 2 diabetes.

1 Department of Bioengineering and Therapeutic Sciences, University of California, School of Pharmacy, San Francisco (UCSF), San Francisco, CA 94143, USA.
2 Department of Pharmaceutical Chemistry, School of Pharmacy, UCSF, San Francisco, CA 94143, USA.
3 Department of Microbiology and Immunology, School of Medicine, UCSF, San Francisco, CA 94143, USA.
4 The George Williams Hooper Foundation, School of Medicine, UCSF, San Francisco, CA 94143, USA.
5 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
6 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
7 Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

* These three authors contributed equally to the work described in this manuscript.

{dagger} Present address: Department of Neurology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8575, Japan.

{ddagger} Present address: Partners Center for Personalized Genetic Medicine, Harvard Medical School, Cambridge, MA 02139, USA.

§ Present address: Program in Biological Sciences, University of California, San Francisco, CA 94143, USA.

||To whom correspondence should be addressed. E-mail: frances.brodsky{at}

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