Plasma membrane flipping of Syntaxin-2 regulates its inhibitory action on insulin granule exocytosis

Fei Kang (), Li Xie, Tairan Qin, Yifan Miao, Youhou Kang, Toshimasa Takahashi, Tao Liang, Huanli Xie and Herbert Y. Gaisano ()
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Fei Kang: University of Toronto
Li Xie: University of Toronto
Tairan Qin: University of Toronto
Yifan Miao: University of Toronto
Youhou Kang: University of Toronto
Toshimasa Takahashi: University of Toronto
Tao Liang: University of Toronto
Huanli Xie: University of Toronto
Herbert Y. Gaisano: University of Toronto

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract Enhancing pancreatic β-cell secretion is a primary therapeutic target for type-2 diabetes (T2D). Syntaxin-2 (Stx2) has just been identified to be an inhibitory SNARE for insulin granule exocytosis, holding potential as a treatment for T2D, yet its molecular underpinnings remain unclear. We show that excessive Stx2 recruitment to raft-like granule docking sites at higher binding affinity than pro-fusion syntaxin-1A effectively competes for and inhibits fusogenic SNARE machineries. Depletion of Stx2 in human β-cells improves insulin secretion by enhancing trans-SNARE complex assembly and cis-SNARE disassembly. Using a genetically-encoded reporter, glucose stimulation is shown to induce Stx2 flipping across the plasma membrane, which relieves its suppression of cytoplasmic fusogenic SNARE complexes to promote insulin secretion. Targeting the flipping efficiency of Stx2 profoundly modulates secretion, which could restore the impaired insulin secretion in diabetes. Here, we show that Stx2 acts to assist this precise tuning of insulin secretion in β-cells, including in diabetes.

Date: 2022
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DOI: 10.1038/s41467-022-33986-3

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