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 Li, Xiao Jiang Li

Research output: Contribution to journalArticle

14 Citations (Scopus)

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 b-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.

Original languageEnglish
Pages (from-to)1305-1317
Number of pages13
JournalCellular and Molecular Life Sciences
Volume69
Issue number8
DOIs
Publication statusPublished - Apr 2012
Externally publishedYes

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Keywords

  • Huntingtin
  • Insulin
  • Pancreas
  • Phosphorylation
  • Trafficking

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Molecular Medicine
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Cape, A., Chen, X., Wang, C. E., O'Neill, A., Lin, Y. F., He, J., Xu, X. S., Yi, H., Li, H., Li, S., & Li, X. J. (2012). Loss of huntingtin-associated protein 1 impairs insulin secretion from pancreatic β-cells. Cellular and Molecular Life Sciences, 69(8), 1305-1317. https://doi.org/10.1007/s00018-011-0692-8