The PI(4)P phosphatase Sac2 controls insulin granule docking and release
| Autor: | Sari Sugahara, Beichen Xie, Olof Idevall-Hagren, Phuoc My Nguyen, Yingke Xu, Nikhil R. Gandasi |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Phosphoric monoester hydrolases
Cellbiologi medicine.medical_treatment Phosphatase Endocrinology and Diabetes Biology Article Cell membrane Islets of Langerhans Mice 03 medical and health sciences Pi medicine Animals Humans Insulin Cells Cultured Research Articles 030304 developmental biology 0303 health sciences Cell Membrane Inositol Polyphosphate 5-Phosphatases 030302 biochemistry & molecular biology Granule (cell biology) Cell Biology Cell biology medicine.anatomical_structure Diabetes Mellitus Type 2 Docking (molecular) Endokrinologi och diabetes Biogenesis |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| Popis: | Nguyen et al. find that the PI(4)P phosphatase Sac2 localizes to insulin granules, where it controls granule docking to the plasma membrane. Loss of Sac2 results in impaired insulin secretion, and Sac2 mRNA levels are reduced in type 2 diabetes. Insulin granule biogenesis involves transport to, and stable docking at, the plasma membrane before priming and fusion. Defects in this pathway result in impaired insulin secretion and are a hallmark of type 2 diabetes. We now show that the phosphatidylinositol 4-phosphate phosphatase Sac2 localizes to insulin granules in a substrate-dependent manner and that loss of Sac2 results in impaired insulin secretion. Sac2 operates upstream of granule docking, since loss of Sac2 prevented granule tethering to the plasma membrane and resulted in both reduced granule density and number of exocytic events. Sac2 levels correlated positively with the number of docked granules and exocytic events in clonal β cells and with insulin secretion in human pancreatic islets, and Sac2 expression was reduced in islets from type 2 diabetic subjects. Taken together, we identified a phosphoinositide switch on the surface on insulin granules that is required for stable granule docking at the plasma membrane and impaired in human type 2 diabetes. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|