Septin5 deletion enhances β-cell exocytosis by releasing microtubule-tethered insulin granules onto plasma membrane
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 t...
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| Format: | Article |
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57421-5 |
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| author | 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 Herbert Y. Gaisano |
| author_facet | 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 Herbert Y. Gaisano |
| author_sort | Li Xie |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2700596b6238427e9cfd5eea6896889e |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-2700596b6238427e9cfd5eea6896889e2025-08-20T03:41:49ZengNature PortfolioNature Communications2041-17232025-03-0116111210.1038/s41467-025-57421-5Septin5 deletion enhances β-cell exocytosis by releasing microtubule-tethered insulin granules onto plasma membraneLi Xie0Fei Kang1Tairan Qin2Youhou Kang3Tao Liang4Huanli Xie5Carol D. Froese6Hong Xie7Aaron Au8Christopher M. Yip9William S. Trimble10Herbert Y. Gaisano11Department of Medicine, Temerty Faculty of Medicine, University of TorontoDepartment of Medicine, Temerty Faculty of Medicine, University of TorontoDepartment of Medicine, Temerty Faculty of Medicine, University of TorontoDepartment of Medicine, Temerty Faculty of Medicine, University of TorontoDepartment of Medicine, Temerty Faculty of Medicine, University of TorontoDepartment of Medicine, Temerty Faculty of Medicine, University of TorontoThe program in Cell Biology, Department of Biochemistry, Hospital for Sick Children, University of TorontoThe program in Cell Biology, Department of Biochemistry, Hospital for Sick Children, University of TorontoInstitute of Biomedical Engineering, University of TorontoInstitute of Biomedical Engineering, University of TorontoThe program in Cell Biology, Department of Biochemistry, Hospital for Sick Children, University of TorontoDepartment of Medicine, Temerty Faculty of Medicine, University of TorontoAbstract 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.https://doi.org/10.1038/s41467-025-57421-5 |
| spellingShingle | 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 Herbert Y. Gaisano Septin5 deletion enhances β-cell exocytosis by releasing microtubule-tethered insulin granules onto plasma membrane Nature Communications |
| title | Septin5 deletion enhances β-cell exocytosis by releasing microtubule-tethered insulin granules onto plasma membrane |
| title_full | Septin5 deletion enhances β-cell exocytosis by releasing microtubule-tethered insulin granules onto plasma membrane |
| title_fullStr | Septin5 deletion enhances β-cell exocytosis by releasing microtubule-tethered insulin granules onto plasma membrane |
| title_full_unstemmed | Septin5 deletion enhances β-cell exocytosis by releasing microtubule-tethered insulin granules onto plasma membrane |
| title_short | Septin5 deletion enhances β-cell exocytosis by releasing microtubule-tethered insulin granules onto plasma membrane |
| title_sort | septin5 deletion enhances β cell exocytosis by releasing microtubule tethered insulin granules onto plasma membrane |
| url | https://doi.org/10.1038/s41467-025-57421-5 |
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