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

Yuan, Ting; Annamalai, Karthika; Naik, Shruti; Lupse, Blaz; Geravandi, Shirin; Pal, Anasua; Dobrowolski, Aleksandra; Ghawali, Jaee; Ruhlandt, Marina; Gorrepati, Kanaka Durga Devi; Azizi, Zahra; Lim, Dae Sik; Maedler, Kathrin; Ardestani, Amin

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.

Citation

Yuan, T., Annamalai, K., Naik, S., Lupse, B., Geravandi, S., Pal, A., …Ardestani, A. (2021). The Hippo kinase LATS2 impairs pancreatic β-cell survival in diabetes through the mTORC1-autophagy axis. Nature communications, 12(1), Article 4928. https://doi.org/10.1038/s41467-021-25145-x

• Journal Article Type: Article
• Acceptance Date: Jul 20, 2021
• Online Publication Date: Aug 13, 2021
• Publication Date: Dec 1, 2021
• Deposit Date: Jan 4, 2024
• Publicly Available Date: Jan 5, 2024
• Journal: Nature Communications
• Electronic ISSN: 2041-1723
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 1
• Article Number: 4928
• DOI: https://doi.org/10.1038/s41467-021-25145-x
• Keywords: Apoptosis; Cell biology; Cell death; Endocrine system and metabolic diseases; Endocrinology
• Public URL: https://hull-repository.worktribe.com/output/4461496