The inducible β5i proteasome subunit contributes to proinsulin degradation in GRP94-deficient β-cells and is overexpressed in type 2 diabetes pancreatic islets.

Autor:	Khilji MS; Laboratory of Immuno-endocrinology, Inflammation, Metabolism, and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Bresson SE; Laboratory of Immuno-endocrinology, Inflammation, Metabolism, and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Verstappen D; Laboratory of Immuno-endocrinology, Inflammation, Metabolism, and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.; Radboud Universiteit, Nijmegen, The Netherlands., Pihl C; Laboratory of Immuno-endocrinology, Inflammation, Metabolism, and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Andersen PAK; Laboratory of Immuno-endocrinology, Inflammation, Metabolism, and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Agergaard JB; Laboratory of Immuno-endocrinology, Inflammation, Metabolism, and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Dahlby T; Laboratory of Immuno-endocrinology, Inflammation, Metabolism, and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Bryde TH; Laboratory of Immuno-endocrinology, Inflammation, Metabolism, and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Klindt K; Laboratory of Immuno-endocrinology, Inflammation, Metabolism, and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Nielsen CK; Laboratory of Immuno-endocrinology, Inflammation, Metabolism, and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Walentinsson A; Translational Science and Experimental Medicine, Early Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Zivkovic D; Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique, Université de Toulouse, Toulouse, France., Bousquet MP; Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique, Université de Toulouse, Toulouse, France., Tyrberg B; Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden., Richardson SJ; Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, United Kingdom., Morgan NG; Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, United Kingdom., Mandrup-Poulsen T; Laboratory of Immuno-endocrinology, Inflammation, Metabolism, and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Marzec MT; Laboratory of Immuno-endocrinology, Inflammation, Metabolism, and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Jazyk:	angličtina
Zdroj:	American journal of physiology. Endocrinology and metabolism [Am J Physiol Endocrinol Metab] 2020 Jun 01; Vol. 318 (6), pp. E892-E900. Date of Electronic Publication: 2020 Apr 07.
DOI:	10.1152/ajpendo.00372.2019
Abstrakt:	Proinsulin is a misfolding-prone protein, and its efficient breakdown is critical when β-cells are confronted with high-insulin biosynthetic demands, to prevent endoplasmic reticulum stress, a key trigger of secretory dysfunction and, if uncompensated, apoptosis. Proinsulin degradation is thought to be performed by the constitutively expressed standard proteasome, while the roles of other proteasomes are unknown. We recently demonstrated that deficiency of the proinsulin chaperone glucose-regulated protein 94 (GRP94) causes impaired proinsulin handling and defective insulin secretion associated with a compensated endoplasmic reticulum stress response. Taking advantage of this model of restricted folding capacity, we investigated the role of different proteasomes in proinsulin degradation, reasoning that insulin secretory dynamics require an inducible protein degradation system. We show that the expression of only one enzymatically active proteasome subunit, namely, the inducible β5i-subunit, was increased in GRP94 CRISPR/Cas9 knockout (KO) cells. Additionally, the level of β5i-containing intermediate proteasomes was significantly increased in these cells, as was β5i-related chymotrypsin-like activity. Moreover, proinsulin levels were restored in GRP94 KO upon β5i small interfering RNA-mediated knockdown. Finally, the fraction of β-cells expressing the β5i-subunit is increased in human islets from type 2 diabetes patients. We conclude that β5i is an inducible proteasome subunit dedicated to the degradation of mishandled proinsulin.
Databáze:	MEDLINE
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