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Plasma membrane flipping of Syntaxin-2 regulates its inhibitory action on insulin granule exocytosis
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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9622911/ https://www.ncbi.nlm.nih.gov/pubmed/36316316 http://dx.doi.org/10.1038/s41467-022-33986-3 |
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author | Kang, Fei Xie, Li Qin, Tairan Miao, Yifan Kang, Youhou Takahashi, Toshimasa Liang, Tao Xie, Huanli Gaisano, Herbert Y. |
author_facet | Kang, Fei Xie, Li Qin, Tairan Miao, Yifan Kang, Youhou Takahashi, Toshimasa Liang, Tao Xie, Huanli Gaisano, Herbert Y. |
author_sort | Kang, Fei |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9622911 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-96229112022-11-02 Plasma membrane flipping of Syntaxin-2 regulates its inhibitory action on insulin granule exocytosis Kang, Fei Xie, Li Qin, Tairan Miao, Yifan Kang, Youhou Takahashi, Toshimasa Liang, Tao Xie, Huanli Gaisano, Herbert Y. Nat Commun Article 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. Nature Publishing Group UK 2022-10-31 /pmc/articles/PMC9622911/ /pubmed/36316316 http://dx.doi.org/10.1038/s41467-022-33986-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Kang, Fei Xie, Li Qin, Tairan Miao, Yifan Kang, Youhou Takahashi, Toshimasa Liang, Tao Xie, Huanli Gaisano, Herbert Y. Plasma membrane flipping of Syntaxin-2 regulates its inhibitory action on insulin granule exocytosis |
title | Plasma membrane flipping of Syntaxin-2 regulates its inhibitory action on insulin granule exocytosis |
title_full | Plasma membrane flipping of Syntaxin-2 regulates its inhibitory action on insulin granule exocytosis |
title_fullStr | Plasma membrane flipping of Syntaxin-2 regulates its inhibitory action on insulin granule exocytosis |
title_full_unstemmed | Plasma membrane flipping of Syntaxin-2 regulates its inhibitory action on insulin granule exocytosis |
title_short | Plasma membrane flipping of Syntaxin-2 regulates its inhibitory action on insulin granule exocytosis |
title_sort | plasma membrane flipping of syntaxin-2 regulates its inhibitory action on insulin granule exocytosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9622911/ https://www.ncbi.nlm.nih.gov/pubmed/36316316 http://dx.doi.org/10.1038/s41467-022-33986-3 |
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