Inhibition of PHLPP1/2 phosphatases rescues pancreatic beta-cells in diabetes

• Type of Material: Article
• Authors: Blaz Lupse, University of Bremen; Karthika Annamalai, University of Bremen; Hazem Ibrahim, University of Bremen; Supreet Kaur, University of Bremen; Shirin Geravandi, University of Bremen; Bhavishya Sarma, University of Bremen; Anasua Pal, University of Bremen; Sushil Awal, University of Bremen; Arundhati Joshi, University of Bremen; Sahar Rafizadeh, University of Bremen; Murali Krishna Madduri, University of Bremen; Mona Khazaei, University of Bremen; Huan Liu, University of Bremen; Ting Yuan, University of Bremen; Wei He, University of Bremen; Kanaka Durga Devi Gorrepati, University of Bremen; Zahra Azizi, University of Bremen; Qi Qi, Emory University; Keqiang Ye, Emory University; Jose Oberholzer, University of Virginia; Kathrin Maedler, University of Bremen; Amin Ardestani, University of Bremen
• Language: English
• Date: 2021-08-03
• Publisher: CELL PRESS
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 The Authors.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.celrep.2021.109490
• Title of Journal or Parent Work: CELL REPORTS
• Volume: 36
• Issue: 5
• Start Page: 109490
• End Page: 109490
• Keywords: ACTIVATION; TUMOR-SUPPRESSOR; SIGNALING PATHWAYS; SURVIVAL; Cell Biology; Science & Technology; REPEAT PROTEIN PHOSPHATASE; ER STRESS; KINASE; PTEN; AKT ACTIVITY; Life Sciences & Biomedicine; DELETION PROTECTS

Abstract

Pancreatic β-cell failure is the key pathogenic element of the complex metabolic deterioration in type 2 diabetes (T2D); its underlying pathomechanism is still elusive. Here, we identify pleckstrin homology domain leucine-rich repeat protein phosphatases 1 and 2 (PHLPP1/2) as phosphatases whose upregulation leads to β-cell failure in diabetes. PHLPP levels are highly elevated in metabolically stressed human and rodent diabetic β-cells. Sustained hyper-activation of mechanistic target of rapamycin complex 1 (mTORC1) is the primary mechanism of the PHLPP upregulation linking chronic metabolic stress to ultimate β-cell death. PHLPPs directly dephosphorylate and regulate activities of β-cell survival-dependent kinases AKT and MST1, constituting a regulatory triangle loop to control β-cell apoptosis. Genetic inhibition of PHLPPs markedly improves β-cell survival and function in experimental models of diabetes in vitro, in vivo, and in primary human T2D islets. Our study presents PHLPPs as targets for functional regenerative therapy of pancreatic β cells in diabetes.