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CASK modulates the assembly and function of the Mint1/Munc18-1 complex to regulate insulin secretion

Zhe Zhang1, Wei Li2, Guang Yang1,3

  • 1State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China.

Cell Discovery
|December 15, 2020
PubMed

Insights

Calcium/calmodulin-dependent protein serine kinase (CASK) regulates insulin secretion by forming a complex with Mint1 and Munc18-1. This CASK-Mint1-Munc18 signaling axis is crucial for vesicle fusion and glucose-stimulated insulin release in beta cells.

Area of Science:

  • Molecular biology
  • Cell biology
  • Endocrinology

Background:

  • Calcium/calmodulin-dependent protein serine kinase (CASK) is known for its role in neuronal vesicle transport.
  • Its function in non-neuronal systems, like insulin secretion, is less understood.

Purpose of the Study:

  • To investigate the role of CASK in regulating insulin secretion from pancreatic beta cells.
  • To elucidate the molecular mechanism of CASK in insulin release.

Main Methods:

  • CASK depletion in mouse islets and beta cells.
  • Analysis of insulin secretion and vesicle docking/fusion.
  • Crystal structure determination of the CASK/Mint1 complex.
  • Investigation of ternary complex formation involving CASK, Mint1, and Munc18-1.

Main Results:

  • CASK depletion significantly reduced insulin secretion and vesicle docking/fusion.
  • CASK forms a glucose-regulated ternary complex with Mint1 and Munc18-1 in beta cells.
  • The crystal structure revealed Mint1's unique whip-like structure interacting with CASK, critical for ternary complex assembly and Munc18-1 localization.

Conclusions:

  • CASK is a key regulator of insulin secretion in pancreatic beta cells.
  • The CASK-Mint1 interaction is essential for forming the CASK-Mint1-Munc18-1 complex, controlling Munc18-1 localization and insulin release.
  • This study reveals the molecular basis of the CASK-Mint1-Munc18 signaling axis in insulin secretion.

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