The inducible β5i proteasome subunit contributes to proinsulin degradation in GRP94-deficient β-cells and is overexpressed in type 2 diabetes pancreatic islets
| Autor: | Michal Marzec, Sarah J. Richardson, Kristian Klindt, Anna Walentinsson, Marie-Pierre Bousquet, Jette Bach Agergaard, Thomas Mandrup-Poulsen, Noel G. Morgan, Phillip Alexander Keller Andersen, Tenna Holgersen Bryde, Christian Kronborg Nielsen, Tina Dahlby, Dusan Zivkovic, Muhammad Saad Khilji, Celina Pihl, Björn Tyrberg, Sophie Emilie Bresson, Danielle Verstappen |
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| Přispěvatelé: | Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty endocrine system Proteasome Endopeptidase Complex Protein Folding Physiology Endocrinology Diabetes and Metabolism medicine.medical_treatment Protein subunit [SDV]Life Sciences [q-bio] GRP94 Protein degradation proinsulin degradation restoration of proinsulin 03 medical and health sciences Gene Knockout Techniques Islets of Langerhans 0302 clinical medicine Physiology (medical) Internal medicine Insulin-Secreting Cells Insulin Secretion medicine Animals Humans Proinsulin Membrane Glycoproteins biology Chemistry Pancreatic islets Insulin Endoplasmic reticulum Endoplasmic Reticulum-Associated Degradation Middle Aged β5i Endoplasmic Reticulum Stress Cell biology Rats 030104 developmental biology Endocrinology medicine.anatomical_structure proteasome Proteasome Diabetes Mellitus Type 2 030220 oncology & carcinogenesis Chaperone (protein) biology.protein Female |
| Zdroj: | American Journal of Physiology. Endocrinology Metabolism and Gastrointestinal Physiology American Journal of Physiology. Endocrinology Metabolism and Gastrointestinal Physiology, 2020, 318 (6), pp.e892-e900. ⟨10.1152/ajpendo.00372.2019⟩ |
| ISSN: | 1522-1555 0363-6100 |
| Popis: | 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: | OpenAIRE |
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