{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T17:26:47Z","timestamp":1768584407492,"version":"3.49.0"},"reference-count":27,"publisher":"American Physiological Society","issue":"6","funder":[{"name":"The Punjab Educational Endowment Fund"},{"DOI":"10.13039\/100015223","name":"Danish Diabetes Academy","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100015223","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004954","name":"Augustinus Fonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004954","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001648","name":"European Foundation for the Study of Diabetes","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001648","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Vissing Fonden"},{"name":"Bjarne jansen Fonden"},{"name":"Kristen og Freddy Johansens Fond"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Endocrinology and Metabolism"],"published-print":{"date-parts":[[2020,6,1]]},"abstract":"<jats:p> Proinsulin is a misfolding-prone protein, and its efficient breakdown is critical when \u03b2-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 \u03b25i-subunit, was increased in GRP94 CRISPR\/Cas9 knockout (KO) cells. Additionally, the level of \u03b25i-containing intermediate proteasomes was significantly increased in these cells, as was \u03b25i-related chymotrypsin-like activity. Moreover, proinsulin levels were restored in GRP94 KO upon \u03b25i small interfering RNA-mediated knockdown. Finally, the fraction of \u03b2-cells expressing the \u03b25i-subunit is increased in human islets from type 2 diabetes patients. We conclude that \u03b25i is an inducible proteasome subunit dedicated to the degradation of mishandled proinsulin. <\/jats:p>","DOI":"10.1152\/ajpendo.00372.2019","type":"journal-article","created":{"date-parts":[[2020,4,7]],"date-time":"2020-04-07T19:03:51Z","timestamp":1586286231000},"page":"E892-E900","source":"Crossref","is-referenced-by-count":10,"title":["The inducible \u03b25i proteasome subunit contributes to proinsulin degradation in GRP94-deficient \u03b2-cells and is overexpressed in type 2 diabetes pancreatic islets"],"prefix":"10.1152","volume":"318","author":[{"given":"Muhammad Saad","family":"Khilji","sequence":"first","affiliation":[{"name":"Laboratory of Immuno-endocrinology, Inflammation, Metabolism, and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophie Emilie","family":"Bresson","sequence":"additional","affiliation":[{"name":"Laboratory of 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