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

posted on 04.12.2020, 17:22 by Bas Brouwers, Ilaria Coppola, Katlijn Vints, Bastian Dislich, Nathalie Jouvet, Leentje Van Lommel, Charlotte Segers, Natalia V. Gounko, Lieven Thorrez, Frans Schuit, Stefan F. Lichtenthaler, Jennifer L. Estall, Jeroen Declercq, Bruno Ramos-Molina, John W.M. Creemers
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.


This work was supported by the FWO Vlaanderen (grant number G0B0617N) and by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy– ID 390857198). JLE is a Chercheur-boursier from the FRQS and her research was supported by a grant from the CIHR (PJT-148771). BRM was supported by the Miguel Servet Type I program (CP19/00098) from the Institute of Health Carlos III (ISCIII), and co-financed by the European Regional Development Fund. BB and IC were supported by predoctoral fellowships from the FWO Vlaanderen.