The Hippo kinase LATS2 impairs pancreatic ß-cell survival in diabetes through the mTORC1-autophagy axis.
Nat Commun
; 12(1): 4928, 2021 08 13.
Article
em En
| MEDLINE
| ID: mdl-34389720
ABSTRACT
Diabetes results from a decline in functional pancreatic ß-cells, but the molecular mechanisms underlying the pathological ß-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 ß-cell apoptosis and impaired function. LATS2 deficiency in ß-cells and primary isolated human islets as well as ß-cell specific LATS2 ablation in mice improves ß-cell viability, insulin secretion and ß-cell mass and ameliorates diabetes development. LATS2 activates mechanistic target of rapamycin complex 1 (mTORC1), a physiological suppressor of autophagy, in ß-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 ß-cell apoptosis triggered by impaired autophagy suggesting an existence of a stress-sensitive multicomponent cellular loop coordinating ß-cell compensation and survival. Our data reveal an important role for LATS2 in pancreatic ß-cell turnover and suggest LATS2 as a potential therapeutic target to improve pancreatic ß-cell survival and function in diabetes.
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1
Base de dados:
MEDLINE
Assunto principal:
Autofagia
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Proteínas Serina-Treonina Quinases
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Proteínas Supressoras de Tumor
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Diabetes Mellitus
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Células Secretoras de Insulina
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Alvo Mecanístico do Complexo 1 de Rapamicina
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article