The F-actin modifier villin regulates insulin granule dynamics and exocytosis downstream of islet cell autoantigen 512
| Autor: | Peter Hoboth, Oliver Otto, B. P. Mulligan, Michele Solimena, Tobias Hildebrandt, Desiree M. Schumann, Anke Sönmez, Maik Herbig, Michael Meyer-Hermann, Jaber Dehghany, Hassan Mziaut, Carla Münster, Anna Ivanova, Yannis Kalaidzidis, Jochen Guck |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
endocrine system lcsh:Internal medicine endocrine system diseases OGTT oral glucose tolerance test medicine.medical_treatment macromolecular substances digestive system Exocytosis F-actin Ica512 03 medical and health sciences Villin PTPRN RT-DC real-time deformability cytometry medicine Insulin Secretion SG secretory granules D diffusion coefficient lcsh:RC31-1245 Molecular Biology Actin D Diffusion Coefficient Egfp Enhanced Green Fluorescent Protein Granules Ipgtt Intraperitoneal Glucose Tolerance Test Ivgtt Intravenous Glucose Tolerance Test Ica512 Islet Cell Autoantigen Ogtt Oral Glucose T geography geography.geographical_feature_category SE standard error biology Cortical actin cytoskeleton Cell Biology Islet EGFP enhanced green fluorescent protein Cell biology Ica512 islet cell autoantigen 030104 developmental biology Biochemistry IVGTT intravenous glucose tolerance test IPGTT intraperitoneal glucose tolerance test biology.protein Original Article TIRFM total internal reflection fluorescence microscopy |
| Zdroj: | Molecular Metabolism, Vol 5, Iss 8, Pp 656-668 (2016) Mol. Metab. 5, 656-68 (2016) Molecular Metabolism |
| ISSN: | 2212-8778 |
| Popis: | Objective Insulin release from pancreatic islet β cells should be tightly controlled to avoid hypoglycemia and insulin resistance. The cortical actin cytoskeleton is a gate for regulated exocytosis of insulin secretory granules (SGs) by restricting their mobility and access to the plasma membrane. Prior studies suggest that SGs interact with F-actin through their transmembrane cargo islet cell autoantigen 512 (Ica512) (also known as islet antigen 2/Ptprn). Here we investigated how Ica512 modulates SG trafficking and exocytosis. Methods Transcriptomic changes in Ica512−/− mouse islets were analyzed. Imaging as well as biophysical and biochemical methods were used to validate if and how the Ica512-regulated gene villin modulates insulin secretion in mouse islets and insulinoma cells. Results The F-actin modifier villin was consistently downregulated in Ica512−/− mouse islets and in Ica512-depleted insulinoma cells. Villin was enriched at the cell cortex of β cells and dispersed villin−/− islet cells were less round and less deformable. Basal mobility of SGs in villin-depleted cells was enhanced. Moreover, in cells depleted either of villin or Ica512 F-actin cages restraining cortical SGs were enlarged, basal secretion was increased while glucose-stimulated insulin release was blunted. The latter changes were reverted by overexpressing villin in Ica512-depleted cells, but not vice versa. Conclusion Our findings show that villin controls the size of the F-actin cages restricting SGs and, thus, regulates their dynamics and availability for exocytosis. Evidence that villin acts downstream of Ica512 also indicates that SGs directly influence the remodeling properties of the cortical actin cytoskeleton for tight control of insulin secretion. Highlights • Ica512-depletion reduces the genetic expression of the F-actin modifier villin. • Villin-depletion enhances basal insulin granule mobility and exocytosis. • Villin regulates the size of actin cages restraining insulin granules. • Villin acts downstream of insulin granule cargo Ica512. • The Ica512-villin genetic link enables granules to control cytoskeleton plasticity. |
| Databáze: | OpenAIRE |
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