PDI is an essential redox-sensitive activator of PERK during the unfolded protein response (UPR)

• Published in: Cell death & disease 2017-08, Vol.8 (8), p.e2986-e2986
• Main Authors: Kranz, Philip, Neumann, Fabian, Wolf, Alexandra, Classen, Fabian, Pompsch, Mosche, Ocklenburg, Tobias, Baumann, Jennifer, Janke, Kirsten, Baumann, Melanie, Goepelt, Kirsten, Riffkin, Helena, Metzen, Eric, Brockmeier, Ulf
• Format: Article
• Language: English
• Subjects: 631/45/607/1168; 631/67/1059; 631/80/470; 631/80/86/2366; Activating Transcription Factor 6 - genetics; Activating Transcription Factor 6 - metabolism; Antibodies; Apoptosis; Apoptosis - genetics; Apoptosis - physiology; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell death; Cell Line, Tumor; Cell Survival - genetics; Cell Survival - physiology; Colon; Colorectal cancer; eIF-2 kinase; eIF-2 Kinase - genetics; eIF-2 Kinase - metabolism; Endoplasmic reticulum; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum Stress - genetics; Endoplasmic Reticulum Stress - physiology; Endoribonucleases - genetics; Endoribonucleases - metabolism; HCT116 Cells; Humans; Hypoxia; Immunology; Kinases; Life Sciences; Original; original-article; Oxidation; Oxidation-Reduction; Procollagen-Proline Dioxygenase - genetics; Procollagen-Proline Dioxygenase - metabolism; Protein disulfide-isomerase; Protein Disulfide-Isomerases - genetics; Protein Disulfide-Isomerases - metabolism; Protein folding; Protein kinase R; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Signal transduction; Signal Transduction - genetics; Signal Transduction - physiology; Thiol oxidoreductase; Unfolded Protein Response - genetics; Unfolded Protein Response - physiology
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2017.369

Endoplasmic reticulum (ER) stress leads to activation of the unfolded protein response (UPR) that results in transient suppression of protein translation to allow recovery but leads to cell death when stress cannot be resolved. Central to initiation of the UPR is the activation of the ER transmembrane kinase protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). Here we report that the thiol oxidoreductase ERp57 and protein disulfide isomerase-A1 (PDI), which belong to the same family of luminal ER oxidoreductases, have strikingly opposing roles in the regulation of PERK function. In HCT116 colon carcinoma cells, lentiviral depletion of ERp57 resulted in oxidation of PDI and activation of PERK, whereas depletion or chemical inhibition of PDI reduced PERK signaling and sensitized the cancer cells to hypoxia and ER stress. We conclude that oxidized PDI acts as a PERK activator, whereas ERp57 keeps PDI in a reduced state in the absence of ER stress. Thus, our study defines a new interface between metabolic redox signaling and PERK-dependent activation of the UPR and has the potential to influence future cancer therapies that target PERK signaling.