PDI is an essential redox-sensitive activator of PERK during the unfolded protein response (UPR).
Cell Death Dis
; 8(8): e2986, 2017 08 10.
Article
em En
| MEDLINE
| ID: mdl-28796255
ABSTRACT
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.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Pró-Colágeno-Prolina Dioxigenase
/
Isomerases de Dissulfetos de Proteínas
/
EIF-2 Quinase
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Resposta a Proteínas não Dobradas
Tipo de estudo:
Diagnostic_studies
Limite:
Humans
Idioma:
En
Revista:
Cell Death Dis
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Alemanha