| First Author | Yuan T | Year | 2021 |
| Journal | Nat Commun | Volume | 12 |
| Issue | 1 | Pages | 4928 |
| PubMed ID | 34389720 | Mgi Jnum | J:308941 |
| Mgi Id | MGI:6753985 | Doi | 10.1038/s41467-021-25145-x |
| Citation | Yuan T, et al. (2021) The Hippo kinase LATS2 impairs pancreatic beta-cell survival in diabetes through the mTORC1-autophagy axis. Nat Commun 12(1):4928 |
| abstractText | Diabetes results from a decline in functional pancreatic beta-cells, but the molecular mechanisms underlying the pathological beta-cell failure are poorly understood. Here we report that large-tumor suppressor 2 (LATS2), a core component of the Hippo signaling pathway, is activated under diabetic conditions and induces beta-cell apoptosis and impaired function. LATS2 deficiency in beta-cells and primary isolated human islets as well as beta-cell specific LATS2 ablation in mice improves beta-cell viability, insulin secretion and beta-cell mass and ameliorates diabetes development. LATS2 activates mechanistic target of rapamycin complex 1 (mTORC1), a physiological suppressor of autophagy, in beta-cells and genetic and pharmacological inhibition of mTORC1 counteracts the pro-apoptotic action of activated LATS2. We further show a direct interplay between Hippo and autophagy, in which LATS2 is an autophagy substrate. On the other hand, LATS2 regulates beta-cell apoptosis triggered by impaired autophagy suggesting an existence of a stress-sensitive multicomponent cellular loop coordinating beta-cell compensation and survival. Our data reveal an important role for LATS2 in pancreatic beta-cell turnover and suggest LATS2 as a potential therapeutic target to improve pancreatic beta-cell survival and function in diabetes. |
