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

Ting Yuan, Karthika Annamalai, Shruti Naik, Blaz Lupse, Shirin Geravandi, Anasua Pal, Aleksandra Dobrowolski, Jaee Ghawali, Marina Ruhlandt, Kanaka Durga Devi Gorrepati, Zahra Azizi, Dae-Sik Lim, Kathrin Maedler () and Amin Ardestani ()
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Ting Yuan: University of Bremen
Karthika Annamalai: University of Bremen
Shruti Naik: University of Bremen
Blaz Lupse: University of Bremen
Shirin Geravandi: University of Bremen
Anasua Pal: University of Bremen
Aleksandra Dobrowolski: University of Bremen
Jaee Ghawali: University of Bremen
Marina Ruhlandt: University of Bremen
Kanaka Durga Devi Gorrepati: University of Bremen
Zahra Azizi: University of Bremen
Dae-Sik Lim: Department of Biological Sciences, KAIST 291 Daehak-ro, Yuseong-gu
Kathrin Maedler: University of Bremen
Amin Ardestani: University of Bremen

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25145-x

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