title: GILZ overexpression attenuates endoplasmic reticulum stress-mediated cell death via the activation of mitochondrial oxidative phosphorylation.
abstract: The Glucocorticoïd-induced leucine zipper (GILZ) protein has profound anti-inflammatory activities in haematopoietic cells. GILZ regulates numerous signal transduction pathways involved in proliferation and survival of normal and neoplastic cells. Here, we have demonstrated the potential of GILZ in alleviating apoptosis induced by ER stress inducers. Whereas the glucocorticoid, dexamethasone, protects from tunicamycin-induced cell death, silencing endogeneous GILZ in dexamethasone-treated cancer cells alter the capacity of glucocorticoids to protect from tunicamycin-mediated apoptosis. Under ER stress conditions, overexpression of GILZ significantly reduced activation of mitochondrial pathway of apoptosis by maintaining Bcl-xl level. GILZ protein affects the UPR signaling shifting the balance towards pro-survival signals as judged by down-regulation of CHOP, ATF4, XBP1s mRNA and increase in GRP78 protein level. Interestingly, GILZ sustains high mitochondrial OXPHOS during ER stress and cytoprotection mediated by GILZ is abolished in cells depleted of mitochondrial DNA, which are OXPHOS-deficient. These findings reveal a new role of GILZ, which acts as a cytoprotector against ER stress through a pathway involving mitochondrial OXPHOS.
authors.affiliation: INSERM UMR-S 1172, Université de Lille, 1 Place Verdun F-59045 Cedex, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: André
authors.affiliation: CHU Lille, Banque de Tissus & Biologie Cellulaire -Thérapie Cellulaire, F-59000 Lille France.
authors.forename: Paola
authors.initials: P
authors.lastname: Corazao-Rozas
authors.affiliation: INSERM UMR-S 1172, Université de Lille, 1 Place Verdun F-59045 Cedex, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Idziorek
authors.affiliation: INSERM UMR-S 1172, Université de Lille, 1 Place Verdun F-59045 Cedex, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Quesnel
authors.affiliation: INSERM UMR-S 1172, Université de Lille, 1 Place Verdun F-59045 Cedex, France.
authors.forename: Jérome
authors.initials: J
authors.lastname: Kluza
authors.affiliation: INSERM UMR-S 1172, Université de Lille, 1 Place Verdun F-59045 Cedex, France; CHU Lille, Banque de Tissus & Biologie Cellulaire -Thérapie Cellulaire, F-59000 Lille France. Electronic address: philippe.marchetti@inserm.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Marchetti
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation; D058767:Protein Unfolding; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C404226:TSC22D3 protein, human; D014157:Transcription Factors
keywords: Apoptosis; Cancer cell metabolism; Glucocorticoids; Mitochondria; TSC-22