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Loss of huntingtin-associated protein 1 impairs insulin secretion from pancreatic β-cells

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Abstract

Hap1 was originally identified as a neuronal protein that interacts with huntingtin, the Huntington’s disease (HD) protein. Later studies revealed that Hap1 participates in intracellular trafficking in neuronal cells and that this trafficking function can be adversely affected by mutant huntingtin. Hap1 is also present in pancreatic β-cells and other endocrine cells; however, the role of Hap1 in these endocrine cells remains unknown. Using the Cre-loxP system, we generated conditional Hap1 knockout mice to selectively deplete the expression of Hap1 in mouse pancreatic β-cells. Mutant mice with Hap1 deficiency in pancreatic β-cells had impaired glucose tolerance and decreased insulin release in response to intraperitoneally injected glucose. Using cultured pancreatic β-cell lines and isolated mouse pancreatic islets, we confirmed that decreasing Hap1 could reduce glucose-mediated insulin release. Electron microscopy suggested that there was a reduced number of insulin-containing vesicles docked at the plasma membrane of pancreatic islets in Hap1 mutant mice following intraperitoneal glucose injection. Glucose treatment decreased the phosphorylation of Hap1A in cultured β-cells and in mouse pancreatic tissues. Moreover, this glucose treatment increased Hap1’s association with kinesin light chain and dynactin p150, both of which are involved in microtubule-dependent trafficking. These studies suggest that Hap1 is important for insulin release from β-cells via dephosphorylation that can regulate its intracellular trafficking function.

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Acknowledgments

This work was supported by NIH Grants NS036232 (X.J.L.) and NS045016 (S.H.L.). We thank Cheryl T. Strauss for her critical reading of the manuscript.

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The authors report no conflicts of interest.

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Authors and Affiliations

  1. Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA, 30322, USA

    Austin Cape, Chuan-En Wang, Ashley O’Neill, Yung-Feng Lin, Xing-Shun Xu, Shihua Li & Xiao-Jiang Li

  2. Division of Histology and Embryology, Department of Anatomy, Tongji Medical College, Huazhong University of Science Technology, Wuhan, 430030, China

    Xingxing Chen, Jun He & He Li

  3. A Core Facility of Emory University, Suite E106, Cherry L. Emerson Hall, 1521 Dickey Drive, Atlanta, GA, 30322, USA

    Hong Yi

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  1. Austin Cape
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  2. Xingxing Chen
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  3. Chuan-En Wang
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  4. Ashley O’Neill
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Correspondence to Shihua Li or Xiao-Jiang Li.

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Cape, A., Chen, X., Wang, CE. et al. Loss of huntingtin-associated protein 1 impairs insulin secretion from pancreatic β-cells. Cell. Mol. Life Sci. 69, 1305–1317 (2012). https://doi.org/10.1007/s00018-011-0692-8

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  • DOI: https://doi.org/10.1007/s00018-011-0692-8

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