Protein disulfide isomerase A6 controls the decay of IRE1α signaling via disulfide-dependent association

Mol Cell. 2014 Feb 20;53(4):562-576. doi: 10.1016/j.molcel.2014.01.004. Epub 2014 Feb 6.

Abstract

The response to endoplasmic reticulum (ER) stress relies on activation of unfolded protein response (UPR) sensors, and the outcome of the UPR depends on the duration and strength of signal. Here, we demonstrate a mechanism that attenuates the activity of the UPR sensor inositol-requiring enzyme 1α (IRE1α). A resident ER protein disulfide isomerase, PDIA6, limits the duration of IRE1α activity by direct binding to cysteine 148 in the lumenal domain of the sensor, which is oxidized when IRE1 is activated. PDIA6-deficient cells hyperrespond to ER stress with sustained autophosphorylation of IRE1α and splicing of XBP1 mRNA, resulting in exaggerated upregulation of UPR target genes and increased apoptosis. In vivo, PDIA6-deficient C. elegans exhibits constitutive UPR and fails to complete larval development, a program that normally requires the UPR. Thus, PDIA6 activity provides a mechanism that limits UPR signaling and maintains it within a physiologically appropriate range.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3T3 Cells
  • Amino Acid Sequence
  • Animals
  • Caenorhabditis elegans / enzymology*
  • Caenorhabditis elegans Proteins / metabolism*
  • Carrier Proteins / metabolism
  • Cell Proliferation
  • Cysteine / chemistry
  • Disulfides / chemistry
  • Endoplasmic Reticulum / metabolism
  • Gene Expression Regulation, Enzymologic*
  • HEK293 Cells
  • Humans
  • Inositol / chemistry
  • Mice
  • Molecular Sequence Data
  • Oxygen / chemistry
  • Phosphorylation
  • Protein Denaturation
  • Protein Disulfide-Isomerases / metabolism*
  • Protein Folding
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA, Messenger / metabolism
  • Sequence Homology, Amino Acid
  • Signal Transduction

Substances

  • Caenorhabditis elegans Proteins
  • Carrier Proteins
  • Disulfides
  • RNA, Messenger
  • XBP-1 protein, C elegans
  • Inositol
  • Protein-Serine-Threonine Kinases
  • IRE-1 protein, C elegans
  • Pdia6 protein, mouse
  • Protein Disulfide-Isomerases
  • Cysteine
  • Oxygen