The Hippo Kinase Lats2 Impairs Pancreatic Β-Cell Survival in Diabetes Through the Mtorc1-Autophagy Axis Publisher Pubmed



Yuan T^{1, 4} ; Annamalai K¹ ; Naik S¹ ; Lupse B¹ ; Geravandi S¹ ; Pal A¹ ; Dobrowolski A¹ ; Ghawali J¹ ; Ruhlandt M¹ ; Gorrepati KDD¹ ; Azizi Z^{1, 2} ; Lim DS³ ; Maedler K¹ ; Ardestani A^{1, 2} Show Affiliations
Source: Nature Communications Published:2021

Abstract

Diabetes results from a decline in functional pancreatic β-cells, but the molecular mechanisms underlying the pathological β-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 β-cell apoptosis and impaired function. LATS2 deficiency in β-cells and primary isolated human islets as well as β-cell specific LATS2 ablation in mice improves β-cell viability, insulin secretion and β-cell mass and ameliorates diabetes development. LATS2 activates mechanistic target of rapamycin complex 1 (mTORC1), a physiological suppressor of autophagy, in β-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 β-cell apoptosis triggered by impaired autophagy suggesting an existence of a stress-sensitive multicomponent cellular loop coordinating β-cell compensation and survival. Our data reveal an important role for LATS2 in pancreatic β-cell turnover and suggest LATS2 as a potential therapeutic target to improve pancreatic β-cell survival and function in diabetes. © 2021, The Author(s).