Loss of Furin in β cells Induces an mTORC1-ATF4 Anabolic Pathway that Leads to β cell Dysfunction

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Loss of Furin in β cells Induces an mTORC1-ATF4 Anabolic Pathway that Leads to β cell Dysfunction. / Brouwers, Bas; Coppola, Ilaria; Vints, Katlijn; Dislich, Bastian; Van Lommel, Leentje; Segers, Charlotte; Gounko, Natalia V.; Thorrez, Lieven; Schuit, Frans; Lichtenthaler, Stefan F.; Estall, Jennifer L.; Declercq, Jeroen; Ramos-Molina, Bruno; Creemers, John W.M.

In: Diabetes, Vol. 70, No. 2, db200474, 04.12.2020, p. 492-503.

Research output: Contribution to journalArticlepeer-review

Harvard

Brouwers, B, Coppola, I, Vints, K, Dislich, B, Van Lommel, L, Segers, C, Gounko, NV, Thorrez, L, Schuit, F, Lichtenthaler, SF, Estall, JL, Declercq, J, Ramos-Molina, B & Creemers, JWM 2020, 'Loss of Furin in β cells Induces an mTORC1-ATF4 Anabolic Pathway that Leads to β cell Dysfunction', Diabetes, vol. 70, no. 2, db200474, pp. 492-503. https://doi.org/10.2337/db20-0474

APA

Brouwers, B., Coppola, I., Vints, K., Dislich, B., Van Lommel, L., Segers, C., Gounko, N. V., Thorrez, L., Schuit, F., Lichtenthaler, S. F., Estall, J. L., Declercq, J., Ramos-Molina, B., & Creemers, J. W. M. (2020). Loss of Furin in β cells Induces an mTORC1-ATF4 Anabolic Pathway that Leads to β cell Dysfunction. Diabetes, 70(2), 492-503. [db200474]. https://doi.org/10.2337/db20-0474

Vancouver

Brouwers B, Coppola I, Vints K, Dislich B, Van Lommel L, Segers C et al. Loss of Furin in β cells Induces an mTORC1-ATF4 Anabolic Pathway that Leads to β cell Dysfunction. Diabetes. 2020 Dec 4;70(2):492-503. db200474. https://doi.org/10.2337/db20-0474

Author

Brouwers, Bas ; Coppola, Ilaria ; Vints, Katlijn ; Dislich, Bastian ; Van Lommel, Leentje ; Segers, Charlotte ; Gounko, Natalia V. ; Thorrez, Lieven ; Schuit, Frans ; Lichtenthaler, Stefan F. ; Estall, Jennifer L. ; Declercq, Jeroen ; Ramos-Molina, Bruno ; Creemers, John W.M. / Loss of Furin in β cells Induces an mTORC1-ATF4 Anabolic Pathway that Leads to β cell Dysfunction. In: Diabetes. 2020 ; Vol. 70, No. 2. pp. 492-503.

Bibtex - Download

@article{dd19383fbd6844af926fbb0feeac0496,
title = "Loss of Furin in β cells Induces an mTORC1-ATF4 Anabolic Pathway that Leads to β cell Dysfunction",
abstract = "FURIN is a proprotein convertase (PC) responsible for proteolytic activation of a wide array of precursor proteins within the secretory pathway. It maps to the PRC1 locus, a type 2 diabetes susceptibility locus, yet its specific role in pancreatic β cells is largely unknown. The aim of this study was to determine the role of FURIN in glucose homeostasis. We show that FURIN is highly expressed in human islets, while PCs that potentially could provide redundancy are expressed at considerably lower levels. β cell-specific Furin knockout (βFurKO) mice are glucose intolerant, due to smaller islets with lower insulin content and abnormal dense core secretory granule morphology. mRNA expression analysis and differential proteomics on βFurKO islets revealed activation of Activating Transcription Factor 4 (ATF4), which was mediated by mammalian target of rapamycin C1 (mTORC1). βFurKO cells show impaired cleavage or shedding of the V-ATPase subunits Ac45 and prorenin receptor (PRR), respectively, and impaired lysosomal acidification. Blocking the V-ATPase pharmacologically in β cells increases mTORC1 activity, suggesting the involvement of the V-ATPase proton pump in the phenotype. Taken together, these results suggest a model of mTORC1-ATF4 hyperactivation and impaired lysosomal acidification in β cells lacking Furin, which causes β cell dysfunction.",
keywords = "Furin",
author = "Bas Brouwers and Ilaria Coppola and Katlijn Vints and Bastian Dislich and {Van Lommel}, Leentje and Charlotte Segers and Gounko, {Natalia V.} and Lieven Thorrez and Frans Schuit and Lichtenthaler, {Stefan F.} and Estall, {Jennifer L.} and Jeroen Declercq and Bruno Ramos-Molina and Creemers, {John W.M.}",
note = "Score=10",
year = "2020",
month = dec,
day = "4",
doi = "10.2337/db20-0474",
language = "English",
volume = "70",
pages = "492--503",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association",
number = "2",

}

RIS - Download

TY - JOUR

T1 - Loss of Furin in β cells Induces an mTORC1-ATF4 Anabolic Pathway that Leads to β cell Dysfunction

AU - Brouwers, Bas

AU - Coppola, Ilaria

AU - Vints, Katlijn

AU - Dislich, Bastian

AU - Van Lommel, Leentje

AU - Segers, Charlotte

AU - Gounko, Natalia V.

AU - Thorrez, Lieven

AU - Schuit, Frans

AU - Lichtenthaler, Stefan F.

AU - Estall, Jennifer L.

AU - Declercq, Jeroen

AU - Ramos-Molina, Bruno

AU - Creemers, John W.M.

N1 - Score=10

PY - 2020/12/4

Y1 - 2020/12/4

N2 - FURIN is a proprotein convertase (PC) responsible for proteolytic activation of a wide array of precursor proteins within the secretory pathway. It maps to the PRC1 locus, a type 2 diabetes susceptibility locus, yet its specific role in pancreatic β cells is largely unknown. The aim of this study was to determine the role of FURIN in glucose homeostasis. We show that FURIN is highly expressed in human islets, while PCs that potentially could provide redundancy are expressed at considerably lower levels. β cell-specific Furin knockout (βFurKO) mice are glucose intolerant, due to smaller islets with lower insulin content and abnormal dense core secretory granule morphology. mRNA expression analysis and differential proteomics on βFurKO islets revealed activation of Activating Transcription Factor 4 (ATF4), which was mediated by mammalian target of rapamycin C1 (mTORC1). βFurKO cells show impaired cleavage or shedding of the V-ATPase subunits Ac45 and prorenin receptor (PRR), respectively, and impaired lysosomal acidification. Blocking the V-ATPase pharmacologically in β cells increases mTORC1 activity, suggesting the involvement of the V-ATPase proton pump in the phenotype. Taken together, these results suggest a model of mTORC1-ATF4 hyperactivation and impaired lysosomal acidification in β cells lacking Furin, which causes β cell dysfunction.

AB - FURIN is a proprotein convertase (PC) responsible for proteolytic activation of a wide array of precursor proteins within the secretory pathway. It maps to the PRC1 locus, a type 2 diabetes susceptibility locus, yet its specific role in pancreatic β cells is largely unknown. The aim of this study was to determine the role of FURIN in glucose homeostasis. We show that FURIN is highly expressed in human islets, while PCs that potentially could provide redundancy are expressed at considerably lower levels. β cell-specific Furin knockout (βFurKO) mice are glucose intolerant, due to smaller islets with lower insulin content and abnormal dense core secretory granule morphology. mRNA expression analysis and differential proteomics on βFurKO islets revealed activation of Activating Transcription Factor 4 (ATF4), which was mediated by mammalian target of rapamycin C1 (mTORC1). βFurKO cells show impaired cleavage or shedding of the V-ATPase subunits Ac45 and prorenin receptor (PRR), respectively, and impaired lysosomal acidification. Blocking the V-ATPase pharmacologically in β cells increases mTORC1 activity, suggesting the involvement of the V-ATPase proton pump in the phenotype. Taken together, these results suggest a model of mTORC1-ATF4 hyperactivation and impaired lysosomal acidification in β cells lacking Furin, which causes β cell dysfunction.

KW - Furin

UR - https://ecm.sckcen.be/OTCS/llisapi.dll/open/41511146

U2 - 10.2337/db20-0474

DO - 10.2337/db20-0474

M3 - Article

VL - 70

SP - 492

EP - 503

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 2

M1 - db200474

ER -

ID: 6977954