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
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/147983
Acceder
id CONICETDig_1ea16f8157adfca85aa3631f8991cf24
oai_identifier_str oai:ri.conicet.gov.ar:11336/147983
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling 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 Técnicas2025-09-29T10:24:30Zoai: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:34982025-09-29 10:24:30.465CONICET 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
_version_ 1844614241541160960
score 13.069144

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