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The Endoplasmic Ret...
The Endoplasmic Reticulum Chaperone Glucose-Regulated Protein 94 is Essential for Proinsulin Handling
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- Mojtaba Ghiasi, Seyed (author)
- Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark
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- Dahlby, Tina (author)
- Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark
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- Hede Andersen, Caroline (author)
- Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark
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- Haataja, Leena (author)
- Univ Michigan, Div Metab Endocrinol & Diabet, Med Ctr, Ann Arbor, MI USA
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- Petersen, Sólrun (author)
- Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark
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- Omar-Hmeadi, Muhmmad (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Yang, Mingyu (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Pihl, Celina (author)
- Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark
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- Emilie Bresson, Sophie (author)
- Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark
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- Saad Khilji, Muhammad (author)
- Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark
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- Klindt, Kristian (author)
- Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark
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- Cheta, Oana (author)
- Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark
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- Perone, Marcelo J (author)
- Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark;Polo Cient Tecnol, Max Planck Soc, Partner Inst, CONICET,Inst Invest Biomed Buenos Aires IBioBA, Buenos Aires, DF, Argentina
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- Tyrberg, Björn (author)
- AstraZeneca, IMED Biotech Unit, Translat Sci Cardiovasc Renal & Metab, Gothenburg, Sweden
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- Prats, Clara (author)
- Univ Copenhagen, Dept Biomed Sci, Ctr Hlth Ageing, Copenhagen, Denmark
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- Barg, Sebastian, 1969- (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi,Barg
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- Tengholm, Anders, 1971- (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Arvan, Peter (author)
- Univ Michigan, Div Metab Endocrinol & Diabet, Med Ctr, Ann Arbor, MI USA
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- Mandrup-Poulsen, Thomas (author)
- Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark
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- Tomasz Marzec, Michal (author)
- Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark
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(creator_code:org_t)
- 2019-01-22
- 2019
- English.
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 68:4, s. 747-760
- Related links:
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https://diabetes.dia...
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https://urn.kb.se/re...
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https://doi.org/10.2...
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Abstract
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- Although endoplasmic reticulum (ER) chaperone binding to mutant proinsulin has been reported, the role of protein chaperones in the handling of wild-type proinsulin is under-investigated. Here, we have explored the importance of glucose regulated protein 94 (GRP94), a prominent ER chaperone known to fold insulin-like growth factors, in proinsulin handling within β-cells. We found that GRP94 co-immunoprecipitated with proinsulin and that inhibition of GRP94 function and/or expression reduced glucose-dependent insulin secretion, shortened proinsulin half-life and lowered intracellular proinsulin and insulin levels. This phenotype was accompanied by post-ER proinsulin misprocessing and higher numbers of enlarged insulin granules that contained amorphic material with reduced immunogold staining for mature insulin. Insulin granule exocytosis was two-fold accelerated but the secreted insulin had diminished bioactivity. Moreover, GRP94 knockdown or knockout in β-cells selectively activated Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK), without increasing apoptosis levels. Finally, GRP94 mRNA was overexpressed in islets from T2D patients. We conclude that GRP94 is a chaperone crucial for proinsulin handling and insulin secretion.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
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Mojtaba Ghiasi, ...
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Dahlby, Tina
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Hede Andersen, C ...
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Haataja, Leena
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Petersen, Sólrun
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Omar-Hmeadi, Muh ...
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show more...
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Yang, Mingyu
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Pihl, Celina
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Emilie Bresson, ...
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Saad Khilji, Muh ...
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Klindt, Kristian
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Cheta, Oana
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Perone, Marcelo ...
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Tyrberg, Björn
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Prats, Clara
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Barg, Sebastian, ...
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Tengholm, Anders ...
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Arvan, Peter
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Mandrup-Poulsen, ...
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Tomasz Marzec, M ...
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Diabetes
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