Endoplasmic reticulum chaperone glucose-regulated protein 94 is essential for proinsulin handling
- Autores
- Ghiasi, Seyed Mojtaba; Dahlby, Tina; Andersen, Caroline Hede; Haataja, Leena; Petersen, Sólrun; Omar-Hmeadi, Muhmmad; Yang, Mingyu; Pihl, Celina; Bresson, Sophie Emilie; Khilji, Muhammad Saad; Klindt, Kristian; Cheta, Oana; Perone, Marcelo Javier; Tyrberg, Björn; Prats, Clara; Barg, Sebastian; Tengholm, Anders; Arvan, Peter; Mandrup-Poulsen, Thomas; Marzec, Michal Tomasz
- Año de publicación
- 2019
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- 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 underinvestigated. 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 b-cells. We found that GRP94 coimmunoprecipitated 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 accelerated twofold, but the secreted insulin had diminished bioactivity. Moreover, GRP94 knockdown or knockout in b-cells selectively activated protein kinase R–like endoplasmic reticulum kinase (PERK), without increasing apoptosis levels. Finally, GRP94 mRNA was overexpressed in islets from patients with type 2 diabetes. We conclude that GRP94 is a chaperone crucial for proinsulin handling and insulin secretion.
Fil: Ghiasi, Seyed Mojtaba. Universidad de Copenhagen; Dinamarca
Fil: Dahlby, Tina. Universidad de Copenhagen; Dinamarca
Fil: Andersen, Caroline Hede. Universidad de Copenhagen; Dinamarca
Fil: Haataja, Leena. University of Michigan; Estados Unidos
Fil: Petersen, Sólrun. Universidad de Copenhagen; Dinamarca
Fil: Omar-Hmeadi, Muhmmad. Uppsala Universitet; Suecia
Fil: Yang, Mingyu. Uppsala Universitet; Suecia
Fil: Pihl, Celina. Universidad de Copenhagen; Dinamarca
Fil: Bresson, Sophie Emilie. Universidad de Copenhagen; Dinamarca
Fil: Khilji, Muhammad Saad. Universidad de Copenhagen; Dinamarca
Fil: Klindt, Kristian. Universidad de Copenhagen; Dinamarca
Fil: Cheta, Oana. Universidad de Copenhagen; Dinamarca
Fil: Perone, Marcelo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Universidad de Copenhagen; Dinamarca
Fil: Tyrberg, Björn. Astrazeneca. IMED Biotech Unit; Suecia
Fil: Prats, Clara. Universidad de Copenhagen; Dinamarca
Fil: Barg, Sebastian. Uppsala Universitet; Suecia
Fil: Tengholm, Anders. Uppsala Universitet; Suecia
Fil: Arvan, Peter. University of Michigan; Estados Unidos
Fil: Mandrup-Poulsen, Thomas. Universidad de Copenhagen; Dinamarca
Fil: Marzec, Michal Tomasz. Universidad de Copenhagen; Dinamarca - Materia
-
GRP94
GP96
Proinsulin
Endoplasmic reticulum - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/147983
Ver los metadatos del registro completo
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Endoplasmic reticulum chaperone glucose-regulated protein 94 is essential for proinsulin handlingGhiasi, Seyed MojtabaDahlby, TinaAndersen, Caroline HedeHaataja, LeenaPetersen, SólrunOmar-Hmeadi, MuhmmadYang, MingyuPihl, CelinaBresson, Sophie EmilieKhilji, Muhammad SaadKlindt, KristianCheta, OanaPerone, Marcelo JavierTyrberg, BjörnPrats, ClaraBarg, SebastianTengholm, AndersArvan, PeterMandrup-Poulsen, ThomasMarzec, Michal TomaszGRP94GP96ProinsulinEndoplasmic reticulumhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Although endoplasmic reticulum (ER) chaperone binding to mutant proinsulin has been reported, the role of protein chaperones in the handling of wild-type proinsulin is underinvestigated. 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 b-cells. We found that GRP94 coimmunoprecipitated 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 accelerated twofold, but the secreted insulin had diminished bioactivity. Moreover, GRP94 knockdown or knockout in b-cells selectively activated protein kinase R–like endoplasmic reticulum kinase (PERK), without increasing apoptosis levels. Finally, GRP94 mRNA was overexpressed in islets from patients with type 2 diabetes. We conclude that GRP94 is a chaperone crucial for proinsulin handling and insulin secretion.Fil: Ghiasi, Seyed Mojtaba. Universidad de Copenhagen; DinamarcaFil: Dahlby, Tina. Universidad de Copenhagen; DinamarcaFil: Andersen, Caroline Hede. Universidad de Copenhagen; DinamarcaFil: Haataja, Leena. University of Michigan; Estados UnidosFil: Petersen, Sólrun. Universidad de Copenhagen; DinamarcaFil: Omar-Hmeadi, Muhmmad. Uppsala Universitet; SueciaFil: Yang, Mingyu. Uppsala Universitet; SueciaFil: Pihl, Celina. Universidad de Copenhagen; DinamarcaFil: Bresson, Sophie Emilie. Universidad de Copenhagen; DinamarcaFil: Khilji, Muhammad Saad. Universidad de Copenhagen; DinamarcaFil: Klindt, Kristian. Universidad de Copenhagen; DinamarcaFil: Cheta, Oana. Universidad de Copenhagen; DinamarcaFil: Perone, Marcelo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Universidad de Copenhagen; DinamarcaFil: Tyrberg, Björn. Astrazeneca. IMED Biotech Unit; SueciaFil: Prats, Clara. Universidad de Copenhagen; DinamarcaFil: Barg, Sebastian. Uppsala Universitet; SueciaFil: Tengholm, Anders. Uppsala Universitet; SueciaFil: Arvan, Peter. University of Michigan; Estados UnidosFil: Mandrup-Poulsen, Thomas. Universidad de Copenhagen; DinamarcaFil: Marzec, Michal Tomasz. Universidad de Copenhagen; DinamarcaAmerican Diabetes Association2019-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/147983Ghiasi, Seyed Mojtaba; Dahlby, Tina; Andersen, Caroline Hede; Haataja, Leena; Petersen, Sólrun; et al.; Endoplasmic reticulum chaperone glucose-regulated protein 94 is essential for proinsulin handling; American Diabetes Association; Diabetes; 68; 4; 4-2019; 747-7600012-17971939-327XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://diabetes.diabetesjournals.org/content/68/4/747.longinfo:eu-repo/semantics/altIdentifier/doi/10.2337/db18-0671info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425875/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:04:44Zoai:ri.conicet.gov.ar:11336/147983instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:04:45.312CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Endoplasmic reticulum chaperone glucose-regulated protein 94 is essential for proinsulin handling |
title |
Endoplasmic reticulum chaperone glucose-regulated protein 94 is essential for proinsulin handling |
spellingShingle |
Endoplasmic reticulum chaperone glucose-regulated protein 94 is essential for proinsulin handling Ghiasi, Seyed Mojtaba GRP94 GP96 Proinsulin Endoplasmic reticulum |
title_short |
Endoplasmic reticulum chaperone glucose-regulated protein 94 is essential for proinsulin handling |
title_full |
Endoplasmic reticulum chaperone glucose-regulated protein 94 is essential for proinsulin handling |
title_fullStr |
Endoplasmic reticulum chaperone glucose-regulated protein 94 is essential for proinsulin handling |
title_full_unstemmed |
Endoplasmic reticulum chaperone glucose-regulated protein 94 is essential for proinsulin handling |
title_sort |
Endoplasmic reticulum chaperone glucose-regulated protein 94 is essential for proinsulin handling |
dc.creator.none.fl_str_mv |
Ghiasi, Seyed Mojtaba Dahlby, Tina Andersen, Caroline Hede Haataja, Leena Petersen, Sólrun Omar-Hmeadi, Muhmmad Yang, Mingyu Pihl, Celina Bresson, Sophie Emilie Khilji, Muhammad Saad Klindt, Kristian Cheta, Oana Perone, Marcelo Javier Tyrberg, Björn Prats, Clara Barg, Sebastian Tengholm, Anders Arvan, Peter Mandrup-Poulsen, Thomas Marzec, Michal Tomasz |
author |
Ghiasi, Seyed Mojtaba |
author_facet |
Ghiasi, Seyed Mojtaba Dahlby, Tina Andersen, Caroline Hede Haataja, Leena Petersen, Sólrun Omar-Hmeadi, Muhmmad Yang, Mingyu Pihl, Celina Bresson, Sophie Emilie Khilji, Muhammad Saad Klindt, Kristian Cheta, Oana Perone, Marcelo Javier Tyrberg, Björn Prats, Clara Barg, Sebastian Tengholm, Anders Arvan, Peter Mandrup-Poulsen, Thomas Marzec, Michal Tomasz |
author_role |
author |
author2 |
Dahlby, Tina Andersen, Caroline Hede Haataja, Leena Petersen, Sólrun Omar-Hmeadi, Muhmmad Yang, Mingyu Pihl, Celina Bresson, Sophie Emilie Khilji, Muhammad Saad Klindt, Kristian Cheta, Oana Perone, Marcelo Javier Tyrberg, Björn Prats, Clara Barg, Sebastian Tengholm, Anders Arvan, Peter Mandrup-Poulsen, Thomas Marzec, Michal Tomasz |
author2_role |
author author author author author author author author author author author author author author author author author author author |
dc.subject.none.fl_str_mv |
GRP94 GP96 Proinsulin Endoplasmic reticulum |
topic |
GRP94 GP96 Proinsulin Endoplasmic reticulum |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3 |
dc.description.none.fl_txt_mv |
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 underinvestigated. 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 b-cells. We found that GRP94 coimmunoprecipitated 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 accelerated twofold, but the secreted insulin had diminished bioactivity. Moreover, GRP94 knockdown or knockout in b-cells selectively activated protein kinase R–like endoplasmic reticulum kinase (PERK), without increasing apoptosis levels. Finally, GRP94 mRNA was overexpressed in islets from patients with type 2 diabetes. We conclude that GRP94 is a chaperone crucial for proinsulin handling and insulin secretion. Fil: Ghiasi, Seyed Mojtaba. Universidad de Copenhagen; Dinamarca Fil: Dahlby, Tina. Universidad de Copenhagen; Dinamarca Fil: Andersen, Caroline Hede. Universidad de Copenhagen; Dinamarca Fil: Haataja, Leena. University of Michigan; Estados Unidos Fil: Petersen, Sólrun. Universidad de Copenhagen; Dinamarca Fil: Omar-Hmeadi, Muhmmad. Uppsala Universitet; Suecia Fil: Yang, Mingyu. Uppsala Universitet; Suecia Fil: Pihl, Celina. Universidad de Copenhagen; Dinamarca Fil: Bresson, Sophie Emilie. Universidad de Copenhagen; Dinamarca Fil: Khilji, Muhammad Saad. Universidad de Copenhagen; Dinamarca Fil: Klindt, Kristian. Universidad de Copenhagen; Dinamarca Fil: Cheta, Oana. Universidad de Copenhagen; Dinamarca Fil: Perone, Marcelo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Universidad de Copenhagen; Dinamarca Fil: Tyrberg, Björn. Astrazeneca. IMED Biotech Unit; Suecia Fil: Prats, Clara. Universidad de Copenhagen; Dinamarca Fil: Barg, Sebastian. Uppsala Universitet; Suecia Fil: Tengholm, Anders. Uppsala Universitet; Suecia Fil: Arvan, Peter. University of Michigan; Estados Unidos Fil: Mandrup-Poulsen, Thomas. Universidad de Copenhagen; Dinamarca Fil: Marzec, Michal Tomasz. Universidad de Copenhagen; Dinamarca |
description |
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 underinvestigated. 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 b-cells. We found that GRP94 coimmunoprecipitated 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 accelerated twofold, but the secreted insulin had diminished bioactivity. Moreover, GRP94 knockdown or knockout in b-cells selectively activated protein kinase R–like endoplasmic reticulum kinase (PERK), without increasing apoptosis levels. Finally, GRP94 mRNA was overexpressed in islets from patients with type 2 diabetes. We conclude that GRP94 is a chaperone crucial for proinsulin handling and insulin secretion. |
publishDate |
2019 |
dc.date.none.fl_str_mv |
2019-04 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/147983 Ghiasi, Seyed Mojtaba; Dahlby, Tina; Andersen, Caroline Hede; Haataja, Leena; Petersen, Sólrun; et al.; Endoplasmic reticulum chaperone glucose-regulated protein 94 is essential for proinsulin handling; American Diabetes Association; Diabetes; 68; 4; 4-2019; 747-760 0012-1797 1939-327X CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/147983 |
identifier_str_mv |
Ghiasi, Seyed Mojtaba; Dahlby, Tina; Andersen, Caroline Hede; Haataja, Leena; Petersen, Sólrun; et al.; Endoplasmic reticulum chaperone glucose-regulated protein 94 is essential for proinsulin handling; American Diabetes Association; Diabetes; 68; 4; 4-2019; 747-760 0012-1797 1939-327X CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/https://diabetes.diabetesjournals.org/content/68/4/747.long info:eu-repo/semantics/altIdentifier/doi/10.2337/db18-0671 info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425875/ |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
American Diabetes Association |
publisher.none.fl_str_mv |
American Diabetes Association |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
reponame_str |
CONICET Digital (CONICET) |
collection |
CONICET Digital (CONICET) |
instname_str |
Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.name.fl_str_mv |
CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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1842269873788420096 |
score |
13.13397 |