TY  - JOUR
A1  - Yuan, Ting
A1  - Annamalai, Karthika
A1  - Naik, Shruti
A1  - Lupse, Blaz
A1  - Geravandi, Shirin
A1  - Pal, Anasua
A1  - Dobrowolski, Aleksandra
A1  - Ghawali, Jaee
A1  - Ruhlandt, Marina
A1  - Gorrepati, Kanaka Durga Devi
A1  - Azizi, Zahra
A1  - Lim, Dae-Sik
A1  - Mädler, Kathrin
A1  - Ardestani, Amin
T1  - The Hippo kinase LATS2 impairs pancreatic β-cell survival in diabetes through the mTORC1-autophagy axis
T2  - Nature Communications
N2  - 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.
KW  - Apoptosis
KW  - Cell biology
KW  - Cell death
KW  - Endocrine system and metabolic diseases
KW  - Endocrinology
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/63255
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-632555
SN  - 2041-1723
N1  - This work was supported by JDRF advanced postdoctoral fellowship (JDRF-APF), the German Research Foundation (DFG) and the European Foundation for the Study of Diabetes (EFSD). Human pancreatic islets were kindly provided by the NIDDK-funded Integrated Islet Distribution Program (IIDP) at City of Hope, NIH Grant # 2UC4DK098085, the JDRF-funded IIDP Islet Award Initiative and through the ECIT Islet for Basic Research program supported by JDRF (JDRF award 31-2008-413).
N1  - Open Access funding enabled and organized by Projekt DEAL.
VL  - 12
IS  - art. 4928
SP  - 1
EP  - 18
PB  - Nature Publishing Group UK
CY  - London [u.a.]
ER  -