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Endoplasmic reticulum stress-activated transcription factor ATF6? requires the disulfide isomerase PDIA5 to modulate chemoresistance.

ABSTRACT: ATF6?, a membrane-anchored transcription factor from the endoplasmic reticulum (ER) that modulates the cellular response to stress as an effector of the unfolded-protein response (UPR), is a key player in the development of tumors of different origin. ATF6? activation has been linked to oncogenic transformation and tumor maintenance; however, the mechanism(s) underlying this phenomenon remains elusive. Here, using a phenotypic small interfering RNA (siRNA) screening, we identified a novel role for ATF6? in chemoresistance and defined the protein disulfide isomerase A5 (PDIA5) as necessary for ATF6? activation upon ER stress. PDIA5 contributed to disulfide bond rearrangement in ATF6? under stress conditions, thereby leading to ATF6? export from the ER and activation of its target genes. Further analysis of the mechanism demonstrated that PDIA5 promotes ATF6? packaging into coat protein complex II (COPII) vesicles and that the PDIA5/ATF6? activation loop is essential to confer chemoresistance on cancer cells. Genetic and pharmacological inhibition of the PDIA5/ATF6? axis restored sensitivity to the drug treatment. This work defines the mechanisms underlying the role of ATF6? activation in carcinogenesis and chemoresistance; furthermore, it identifies PDIA5 as a key regulator ATF6?-mediated cellular functions in cancer.

SUBMITTER: Higa A

PROVIDER: S-EPMC4019026 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Endoplasmic reticulum stress-activated transcription factor ATF6α requires the disulfide isomerase PDIA5 to modulate chemoresistance.

Higa Arisa A Taouji Said S Lhomond Stéphanie S Jensen Devon D Fernandez-Zapico Martin E ME Simpson Jeremy C JC Pasquet Jean-Max JM Schekman Randy R Chevet Eric E

Molecular and cellular biology 20140317 10

ATF6α, a membrane-anchored transcription factor from the endoplasmic reticulum (ER) that modulates the cellular response to stress as an effector of the unfolded-protein response (UPR), is a key player in the development of tumors of different origin. ATF6α activation has been linked to oncogenic transformation and tumor maintenance; however, the mechanism(s) underlying this phenomenon remains elusive. Here, using a phenotypic small interfering RNA (siRNA) screening, we identified a novel role f ...[more]

PMID: 24636989

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Project description:BACKGROUND: Protein disulfide isomerase (PDI), is sorted to be enzymatic chaperone for reconstructing misfolded protein in endoplasmic reticulum lumen. Recently, PDI has been identified as a link between misfolded protein and neuron apoptosis. However, the potential for PDI to be involved in the pathogenesis of prion disease remains unknown. In this study, we propose that PDI may function as a pleiotropic regulator in the cytotoxicity induced by mutated prion proteins and in the pathogenesis of prion diseases. METHODOLOGY/PRINCIPAL FINDINGS: To elucidate potential alterations of PDI in prion diseases, the levels of PDI and relevant apoptotic executors in 263K infected hamsters brain tissues were evaluated with the use of Western blots. Abnormal upregulation of PDI, Grp78 and Grp58 was detected. Dynamic assays of PDI alteration identified that the upregulation of PDI started at the early stage and persistently increased till later stage. Obvious increases of PDI and Grp78 levels were also observed in cultured cells transiently expressing PrP mutants, PrP-KDEL or PrP-PG15, accompanied by significant cytotoxicities. Excessive expression of PDI partially eased ER stress and cell apoptosis caused by accumulation of PrP-KDEL, but had less effect on cytotoxicity induced by PrP-PG15. Knockdown of endogenous PDI significantly amended cytotoxicity of PrP-PG15, but had little influence on that of PrP-KDEL. A series of membrane potential assays found that apoptosis induced by misfolded PrP proteins could be regulated by PDI via mitochondrial dysfunction. Moreover, biotin-switch assays demonstrated active S-nitrosylated modifications of PDI (SNO-PDI) both in the brains of scrapie-infected rodents and in the cells with misfolded PrP proteins. CONCLUSION/SIGNIFICANCE: Current data in this study highlight that PDI and its relevant executors may function as a pleiotropic regulator in the processes of different misfolded PrP proteins and at different stages during prion infection. SNO-PDI may feed as an accomplice for PDI apoptosis.

Dataset Information

Endoplasmic reticulum stress-activated transcription factor ATF6? requires the disulfide isomerase PDIA5 to modulate chemoresistance.

Publications

Endoplasmic reticulum stress-activated transcription factor ATF6α requires the disulfide isomerase PDIA5 to modulate chemoresistance.

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