Wojnacki, JoséLujan, Agustin LeonardoBrouwers, NathalieAranda Vallejo, CarlaBigliani, GonzaloPena Rodriguez, MariaForesti, OmbrettaMalhotra, Vivek2023-11-032023-11-032023Wojnacki J, Lujan AL, Brouwers N, Aranda-Vallejo C, Bigliani G, Pena Rodriguez M, Foresti O, Malhotra V. Tetraspanin-8 sequesters syntaxin-2 to control biphasic release propensity of mucin granules. Nat Commun. 2023 Jun 22;14(1):3710. DOI: 10.1038/s41467-023-39277-92041-1723http://hdl.handle.net/10230/58202Agonist-mediated stimulated pathway of mucin and insulin release are biphasic in which rapid fusion of pre-docked granules is followed by slow docking and fusion of granules from the reserve pool. Here, based on a cell-culture system, we show that plasma membrane-located tetraspanin-8 sequesters syntaxin-2 to control mucin release. Tetraspanin-8 affects fusion of granules during the second phase of stimulated mucin release. The tetraspanin-8/syntaxin-2 complex does not contain VAMP-8, which functions with syntaxin-2 to mediate granule fusion. We suggest that by sequestering syntaxin-2, tetraspanin-8 prevents docking of granules from the reserve pool. In the absence of tetraspanin-8, more syntaxin-2 is available for docking and fusion of granules and thus doubles the quantities of mucins secreted. This principle also applies to insulin release and we suggest a cell type specific Tetraspanin/Syntaxin combination is a general mechanism regulating the fusion of dense core granules.application/pdfeng© The Author(s) 2023. 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/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-023-39277-9ExocytosisSecretionSNAREinfo:eu-repo/semantics/openAccess