title: Protein disulfide isomerase A6 controls the decay of IRE1α signaling via disulfide-dependent association.
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.
authors: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Davide
authors: D
authors: Eletto
authors: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Daniela
authors: D
authors: Eletto
authors: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Devin
authors: D
authors: Dersh
authors: Department of Biology, Drexel University, Philadelphia, PA 19104, USA.
authors: Tali
authors: T
authors: Gidalevitz
authors: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Yair
authors: Y
authors: Argon
mesh_terms: D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D049109:Cell Proliferation; D003545:Cysteine / Q000737:chemistry; D004220:Disulfides / Q000737:chemistry; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006801:Humans; D007294:Inositol / Q000737:chemistry; D051379:Mice; D008969:Molecular Sequence Data; D010100:Oxygen / Q000737:chemistry; D010766:Phosphorylation; D011489:Protein Denaturation; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D004220:Disulfides; D012333:RNA, Messenger; C548541:XBP-1 protein, C elegans; D007294:Inositol; D017346:Protein Serine-Threonine Kinases; C541905:IRE-1 protein, C elegans; C526507:Pdia6 protein, mouse; D019704:Protein Disulfide-Isomerases; D003545:Cysteine; D010100:Oxygen