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Cellular and Molecular Life Sciences

, Volume 69, Issue 8, pp 1305–1317 | Cite as

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

  • Austin Cape
  • Xingxing Chen
  • Chuan-En Wang
  • Ashley O’Neill
  • Yung-Feng Lin
  • Jun He
  • Xing-Shun Xu
  • Hong Yi
  • He Li
  • Shihua LiEmail author
  • Xiao-Jiang LiEmail author
Research article

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.

Keywords

Huntingtin Trafficking Insulin Pancreas Phosphorylation 

Notes

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.

Conflict of interest

The authors report no conflicts of interest.

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Copyright information

© Springer Basel AG 2011

Authors and Affiliations

  • Austin Cape
    • 1
  • Xingxing Chen
    • 2
  • Chuan-En Wang
    • 1
  • Ashley O’Neill
    • 1
  • Yung-Feng Lin
    • 1
  • Jun He
    • 2
  • Xing-Shun Xu
    • 1
  • Hong Yi
    • 3
  • He Li
    • 2
  • Shihua Li
    • 1
    Email author
  • Xiao-Jiang Li
    • 1
    Email author
  1. 1.Department of Human GeneticsEmory University School of MedicineAtlantaUSA
  2. 2.Division of Histology and Embryology, Department of Anatomy, Tongji Medical CollegeHuazhong University of Science TechnologyWuhanChina
  3. 3.A Core Facility of Emory UniversityAtlantaUSA

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