Editors' ChoiceCell Biology

ARC unleashes elastase

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Science Signaling  06 Apr 2021:
Vol. 14, Issue 677, eabi8030
DOI: 10.1126/scisignal.abi8030

An antiapoptotic cytoplasmic protein becomes a proapoptotic nuclear protein in diabetes.

Various cellular stresses contribute to the caspase-dependent death of pancreatic β cells in type 2 diabetes (see Onodera and Scherer). Apoptosis repressor with caspase recruitment domain (ARC) potently inhibits both extrinsic and intrinsic apoptotic pathways. Although cytoplasmic ARC generally promotes β cell survival by inhibiting endoplasmic reticulum (ER) stress–induced apoptosis, McKimpson et al. found that nuclear ARC promoted β cell apoptosis in the context of type 2 diabetes. ARC was present in the nuclei of a small portion of β cells in wild-type mice, but most β cells showed nuclear ARC in several genetic mouse models of type 2 diabetes. Whereas cytoplasmic ARC protected cultured mouse β cells against apoptosis induced by various ER stressors, nuclear ARC enhanced ER stress–induced apoptosis. Through an unknown mechanism, nuclear ARC reduced the expression of several serpina1 transcripts, as well as the secretion of α1-antitrypsin (AAT), an extracellular protease inhibitor that is encoded by these transcripts and primarily targets elastase. Depleting serpina1 transcripts or adding exogenous elastase enhanced ARC-dependent, ER stress–induced cell death, and adding active AAT inhibited it. Nuclear ARC or reductions in AAT reduced cell adhesion independently of apoptosis but treating the cells with a pharmacological inhibitor of elastase restored adhesion. Pancreatic samples from patients with type 2 diabetes and from diabetic mice also showed reductions in AAT, and systemic administration of AAT to diabetic mice reduced β cell death and the loss of pancreatic islets and improved hyperglycemia and glucose tolerance. These findings identify an unexpected role for ARC in promoting β cell death and implicate elastase-mediated loss of adhesion in β cell death in type 2 diabetes.

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