Protein disulfide isomerase A6 (PDIA6) interacts with protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol requiring enzyme (IRE)-1 and inhibits their unfolded protein response signaling. In this study, shRNA silencing of PDIA6 expression in insulin-producing mouse cells reduced insulin production (5-fold) and, consequently, glucose-stimulated insulin secretion (3-4-fold).This inhibition of insulin release was independent of the PDIA6-PERK interaction or PERK activity. Acute inhibition of PERKdid not change the shortterm response of b cells to glucose. Rather, PDIA6 affected insulin secretion bymodulating one of the activities of IRE1. At 11mMglucose and lower, the regulated IRE1- dependent decay (RIDD) of the mRNA activity of IRE1 was activated, but not its X-box binding protein (XBP)-1 splicing activity. In the absence of PDIA6, RIDD activity toward insulin transcripts was enhanced up to 4-fold, as shown bymolecular assays in cultured cells and the use of a fluorescent reporter in intact islets. Such physiologic activation of IRE1 by glucose contrasted with IRE1 activation by chemical stress,whenbothIRE1 activitieswere induced. Thus, whereas the stimulus determines the quality of IRE1 signaling, PDIA6 attenuates multiple enzymatic activities of IRE1, maintaining its signaling within a physiologically tolerable range.

PDIA6 regulates insulin secretion by selectively inhibiting the RIDD activity of IRE1

Eletto D.;Eletto D.;
2016-01-01

Abstract

Protein disulfide isomerase A6 (PDIA6) interacts with protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol requiring enzyme (IRE)-1 and inhibits their unfolded protein response signaling. In this study, shRNA silencing of PDIA6 expression in insulin-producing mouse cells reduced insulin production (5-fold) and, consequently, glucose-stimulated insulin secretion (3-4-fold).This inhibition of insulin release was independent of the PDIA6-PERK interaction or PERK activity. Acute inhibition of PERKdid not change the shortterm response of b cells to glucose. Rather, PDIA6 affected insulin secretion bymodulating one of the activities of IRE1. At 11mMglucose and lower, the regulated IRE1- dependent decay (RIDD) of the mRNA activity of IRE1 was activated, but not its X-box binding protein (XBP)-1 splicing activity. In the absence of PDIA6, RIDD activity toward insulin transcripts was enhanced up to 4-fold, as shown bymolecular assays in cultured cells and the use of a fluorescent reporter in intact islets. Such physiologic activation of IRE1 by glucose contrasted with IRE1 activation by chemical stress,whenbothIRE1 activitieswere induced. Thus, whereas the stimulus determines the quality of IRE1 signaling, PDIA6 attenuates multiple enzymatic activities of IRE1, maintaining its signaling within a physiologically tolerable range.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11386/4755870
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