| First Author | Baghestani S | Year | 2024 |
| Journal | Am J Physiol Cell Physiol | Volume | 327 |
| Issue | 2 | Pages | C462-C476 |
| PubMed ID | 38912736 | Mgi Jnum | J:358343 |
| Mgi Id | MGI:7711382 | Doi | 10.1152/ajpcell.00123.2024 |
| Citation | Baghestani S, et al. (2024) beta-Cell keratin 8 maintains islet mechanical integrity, mitochondrial ultrastructure, and beta-cell glucose transporter 2 plasma membrane targeting. Am J Physiol Cell Physiol 327(2):C462-C476 |
| abstractText | Islet beta-cell dysfunction is an underlying factor for type I diabetes (T1D) development. Insulin sensing and secretion are tightly regulated in beta-cells at multiple subcellular levels. The epithelial intermediate filament (IF) protein keratin (K) 8 is the main beta-cell keratin, constituting the filament network with K18. To identify the cell-autonomous functions of K8 in beta-cells, mice with targeted deletion of beta-cell K8 (K8(flox/flox); Ins-Cre) were analyzed for islet morphology, ultrastructure, and integrity, as well as blood glucose regulation and streptozotocin (STZ)-induced diabetes development. Glucose transporter 2 (GLUT2) localization was studied in beta-cells in vivo and in MIN6 cells with intact or disrupted K8/K18 filaments. Loss of beta-cell K8 leads to a major reduction in K18. Islets without beta-cell K8 are more fragile, and these beta-cells display disjointed plasma membrane organization with less membranous E-cadherin and smaller mitochondria with diffuse cristae. Lack of beta-cell K8 also leads to a reduced glucose-stimulated insulin secretion (GSIS) response in vivo, despite undisturbed systemic blood glucose regulation. K8(flox/flox), Ins-Cre mice have a decreased sensitivity to STZ compared with K8 wild-type mice, which is in line with decreased membranous GLUT2 expression observed in vivo, as GLUT2 is required for STZ uptake in beta-cells. In vitro, MIN6 cell plasma membrane GLUT2 is rescued in cells overexpressing K8/K18 filaments but mistargeted in cells with disrupted K8/K18 filaments. beta-Cell K8 is required for islet and beta-cell structural integrity, normal mitochondrial morphology, and GLUT2 plasma membrane targeting, and has implications on STZ sensitivity as well as systemic insulin responses.NEW & NOTEWORTHY Keratin 8 is the main cytoskeletal protein in the cytoplasmic intermediate filament network in beta-cells. Here for the first time, we assessed the beta-cell autonomous mechanical and nonmechanical roles of keratin 8 in beta-cell function. We demonstrated the importance of keratin 8 in islet and beta-cell structural integrity, maintaining mitochondrial morphology and GLUT2 plasma membrane targeting. |
