| First Author | Rahman MM | Year | 2023 |
| Journal | FASEB J | Volume | 37 |
| Issue | 8 | Pages | e23075 |
| PubMed ID | 37432648 | Mgi Jnum | J:344888 |
| Mgi Id | MGI:7579460 | Doi | 10.1096/fj.202300291RR |
| Citation | Rahman MM, et al. (2023) Genetic ablation of synaptotagmin-9 alters tomosyn-1 function to increase insulin secretion from pancreatic beta-cells improving glucose clearance. FASEB J 37(8):e23075 |
| abstractText | Stimulus-coupled insulin secretion from the pancreatic islet beta-cells involves the fusion of insulin granules to the plasma membrane (PM) via SNARE complex formation-a cellular process key for maintaining whole-body glucose homeostasis. Less is known about the role of endogenous inhibitors of SNARE complexes in insulin secretion. We show that an insulin granule protein synaptotagmin-9 (Syt9) deletion in mice increased glucose clearance and plasma insulin levels without affecting insulin action compared to the control mice. Upon glucose stimulation, increased biphasic and static insulin secretion were observed from ex vivo islets due to Syt9 loss. Syt9 colocalizes and binds with tomosyn-1 and the PM syntaxin-1A (Stx1A); Stx1A is required for forming SNARE complexes. Syt9 knockdown reduced tomosyn-1 protein abundance via proteasomal degradation and binding of tomosyn-1 to Stx1A. Furthermore, Stx1A-SNARE complex formation was increased, implicating Syt9-tomosyn-1-Stx1A complex is inhibitory in insulin secretion. Rescuing tomosyn-1 blocked the Syt9-knockdown-mediated increases in insulin secretion. This shows that the inhibitory effects of Syt9 on insulin secretion are mediated by tomosyn-1. We report a molecular mechanism by which beta-cells modulate their secretory capacity rendering insulin granules nonfusogenic by forming the Syt9-tomosyn-1-Stx1A complex. Altogether, Syt9 loss in beta-cells decreases tomosyn-1 protein abundance, increasing the formation of Stx1A-SNARE complexes, insulin secretion, and glucose clearance. These outcomes differ from the previously published work that identified Syt9 has either a positive or no effect of Syt9 on insulin secretion. Future work using beta-cell-specific deletion of Syt9 mice is key for establishing the role of Syt9 in insulin secretion. |
