Loss of <i>Furin</i> 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, but 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 <i>FURIN</i> is highly expressed in human islets, whereas PCs that potentially could provide redundancy are expressed at considerably lower levels. β-cell-specific <i>Furin</i> knockout (β<i>Fur</i>KO) mice are glucose intolerant as a result of smaller islets with lower insulin content and abnormal dense-core secretory granule morphology. mRNA expression analysis and differential proteomics on β<i>Fur</i>KO islets revealed activation of activating transcription factor 4 (ATF4), which was mediated by mammalian target of rapamycin C1 (mTORC1). β<i>Fur</i>KO cells show impaired cleavage or shedding of vacuolar-type ATPase (V-ATPase) subunits Ac45 and prorenin receptor, respectively, and impaired lysosomal acidification. Blocking V-ATPase pharmacologically in β-cells increased mTORC1 activity, suggesting 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 <i>Furin</i>, causing β-cell dysfunction.