Septin5 deletion enhances β-cell exocytosis by releasing microtubule-tethered insulin granules onto plasma membrane

Li Xie (), Fei Kang (), Tairan Qin, Youhou Kang, Tao Liang, Huanli Xie, Carol D. Froese, Hong Xie, Aaron Au, Christopher M. Yip, William S. Trimble and Herbert Y. Gaisano ()
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Li Xie: University of Toronto
Fei Kang: University of Toronto
Tairan Qin: University of Toronto
Youhou Kang: University of Toronto
Tao Liang: University of Toronto
Huanli Xie: University of Toronto
Carol D. Froese: University of Toronto
Hong Xie: University of Toronto
Aaron Au: University of Toronto
Christopher M. Yip: University of Toronto
William S. Trimble: University of Toronto
Herbert Y. Gaisano: University of Toronto

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Septin5 interacts with SNARE proteins to regulate exocytosis in neurons, but its role in pancreatic β-cells is unknown. Here, we report that Septin5 is abundant in rodent and human β-cells, deletion of which dramatically enhances biphasic glucose-stimulated insulin secretion, including in type 2 diabetes (T2D). Super-resolution imaging shows that Septin5 is preferentially assembled in microtubule-plasma membrane contact sites in a microtubule-dependent manner, which provides discrete harbor for secretory granule anchoring. By decreasing the stability of the cortical microtubule meshwork, Septin5 depletion increases insulin granule dynamics and access to the plasma membrane. Analysis of spatiotemporal coupling of fusion events and localized Ca2+ influx through L-type Ca2+ channels show that Septin5 depletion increases releasable granule pool clustering on Ca2+ channels, previously shown to be impaired in T2D, thus rectifying this T2D defect. Hence, inhibition of Septin5 can improve insulin secretion.

Date: 2025
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DOI: 10.1038/s41467-025-57421-5

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