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Loss of Furin in β cells Induces an mTORC1-ATF4 Anabolic Pathway that Leads to β cell Dysfunction
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posted on 2020-12-04, 17:22 authored 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. CreemersFURIN 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.