Conversion of the death inhibitor ARC to a killer activates pancreatic β cell death in diabetes.

Autor:	McKimpson WM; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Chen Y; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Irving JA; UCL Respiratory Medicine, University College London, London WC1E 6BN, UK; Institute of Structural and Molecular Biology/Birkbeck, University of London, London WC1E 7HX, UK., Zheng M; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Weinberger J; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Tan WLW; Cardiovascular Research Institute, National University Health Systems, Singapore, Singapore; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore., Tiang Z; Cardiovascular Research Institute, National University Health Systems, Singapore, Singapore; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore., Jagger AM; UCL Respiratory Medicine, University College London, London WC1E 6BN, UK; Institute of Structural and Molecular Biology/Birkbeck, University of London, London WC1E 7HX, UK., Chua SC Jr; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Pessin JE; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Foo RS; Cardiovascular Research Institute, National University Health Systems, Singapore, Singapore; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore., Lomas DA; UCL Respiratory Medicine, University College London, London WC1E 6BN, UK; Institute of Structural and Molecular Biology/Birkbeck, University of London, London WC1E 7HX, UK., Kitsis RN; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: richard.kitsis@einsteinmed.org.
Jazyk:	angličtina
Zdroj:	Developmental cell [Dev Cell] 2021 Mar 22; Vol. 56 (6), pp. 747-760.e6. Date of Electronic Publication: 2021 Mar 04.
DOI:	10.1016/j.devcel.2021.02.011
Abstrakt:	Loss of insulin-secreting pancreatic β cells through apoptosis contributes to the progression of type 2 diabetes, but underlying mechanisms remain elusive. Here, we identify a pathway in which the cell death inhibitor ARC paradoxically becomes a killer during diabetes. While cytoplasmic ARC maintains β cell viability and pancreatic architecture, a pool of ARC relocates to the nucleus to induce β cell apoptosis in humans with diabetes and several pathophysiologically distinct mouse models. β cell death results through the coordinate downregulation of serpins (serine protease inhibitors) not previously known to be synthesized and secreted by β cells. Loss of the serpin α 1 -antitrypsin from the extracellular space unleashes elastase, triggering the disruption of β cell anchorage and subsequent cell death. Administration of α 1 -antitrypsin to mice with diabetes prevents β cell death and metabolic abnormalities. These data uncover a pathway for β cell loss in type 2 diabetes and identify an FDA-approved drug that may impede progression of this syndrome. Competing Interests: Declaration of interests David Lomas is an inventor on the patent PCT/GB2019/051761 for a small molecule treatment of antitrypsin deficiency. This small molecule has not been used in this work. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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