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

FASEB J. 2016 Feb;30(2):653-65. doi: 10.1096/fj.15-275883. Epub 2015 Oct 20.


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 PERK did not change the short-term response of β cells to glucose. Rather, PDIA6 affected insulin secretion by modulating one of the activities of IRE1. At 11 mM glucose 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 by molecular 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, when both IRE1 activities were 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.

Keywords: GSIS; unfolded protein response; β-cell metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Actins / metabolism
  • Animals
  • Cell Line
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Gene Silencing
  • Glucose / metabolism
  • Glucose / pharmacology
  • Humans
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Protein Disulfide-Isomerases / genetics
  • Protein Disulfide-Isomerases / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Splicing
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Regulatory Factor X Transcription Factors
  • Thapsigargin / pharmacology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • X-Box Binding Protein 1
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism


  • Actins
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Insulin
  • Membrane Proteins
  • RNA, Messenger
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Xbp1 protein, mouse
  • Thapsigargin
  • Ern2 protein, mouse
  • ERN1 protein, human
  • PERK kinase
  • Protein-Serine-Threonine Kinases
  • eIF-2 Kinase
  • Endoribonucleases
  • PDIA6 protein, human
  • Pdia6 protein, mouse
  • Protein Disulfide-Isomerases
  • Glucose