4.8 Article

The Hippo kinase LATS2 impairs pancreatic β-cell survival in diabetes through the mTORC1-autophagy axis

Journal

NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41467-021-25145-x

Keywords

-

Funding

  1. JDRF advanced postdoctoral fellowship (JDRF-APF)
  2. German Research Foundation (DFG)
  3. European Foundation for the Study of Diabetes (EFSD)
  4. NIDDK
  5. JDRF [31-2008-413]
  6. NIH [2UC4DK098085]

Ask authors/readers for more resources

LATS2, a core component of the Hippo signaling pathway, is activated under diabetic conditions and induces beta-cell failure. Inhibiting LATS2 can improve beta-cell viability and insulin secretion, suggesting it as a potential therapeutic target for improving pancreatic beta-cell survival in diabetes.
Diabetes is characterized by dysfunction and loss of beta-cells, and promoting beta-cell survival is of therapeutic interest. Here the authors show that Large-tumor suppressor 2 (LATS2), a core component of the Hippo signaling pathway, induces beta-cell failure through mTORC1 hyperactivation and autophagic flux suppression. 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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.8
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available