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 Mädler, Amin Ardestani
- 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.
MetadatenAuthor: | 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 Mädler, Amin Ardestani |
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URN: | urn:nbn:de:hebis:30:3-632555 |
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DOI: | https://doi.org/10.1038/s41467-021-25145-x |
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ISSN: | 2041-1723 |
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Parent Title (English): | Nature Communications |
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Publisher: | Nature Publishing Group UK |
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Place of publication: | London [u.a.] |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2021/08/13 |
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Date of first Publication: | 2021/08/13 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2022/04/19 |
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Tag: | Apoptosis; Cell biology; Cell death; Endocrine system and metabolic diseases; Endocrinology |
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Volume: | 12 |
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Issue: | art. 4928 |
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Page Number: | 18 |
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First Page: | 1 |
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Last Page: | 18 |
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Note: | 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). |
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Note: | Open Access funding enabled and organized by Projekt DEAL. |
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HeBIS-PPN: | 494894164 |
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Institutes: | Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 4.0 |
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