Endoplasmic Reticulum Stress-Activated Transcription Factor ATF6α Requires the Disulfide Isomerase PDIA5 To Modulate Chemoresistance
Endoplasmic Reticulum Stress-Activated Transcription Factor ATF6α Requires the Disulfide Isomerase PDIA5 To Modulate Chemoresistance
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DOI：
10.1128/mcb.01484-13
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发表时间：
2014-05-01
影响因子：
5.3
通讯作者：
Chevet, Eric
中科院分区：
文献类型：
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作者：
Higa, Arisa;Taouji, Said;Chevet, Eric
ATF 6 α是一种来自内质网（ER）的膜锚定转录因子，作为未折叠蛋白反应（UPR）的效应子调节细胞对应激的反应，是不同来源肿瘤发展的关键参与者。ATF 6 α激活与致癌转化和肿瘤维持有关;然而，这种现象背后的机制仍然难以捉摸。在这里，使用表型小干扰RNA（siRNA）筛选，我们确定了一个新的作用，ATF 6 α在化疗耐药性和定义的蛋白质二硫键异构酶A5（PDIA 5）作为必要的ATF 6 α激活ER应力。PDIA 5在应激条件下促进ATF 6 α中的二硫键重排，从而导致ATF 6 α从ER输出并激活其靶基因。对该机制的进一步分析表明，PDIA 5促进ATF 6 α包装到外壳蛋白复合物II（COPII）囊泡中，并且PDIA 5/ATF 6 α激活环对于赋予癌细胞化学抗性是必需的。PDIA 5/ATF 6 α轴的遗传和药理学抑制恢复了对药物治疗的敏感性。这项工作定义了ATF 6 α激活在致癌和化疗耐药性中作用的机制;此外，它还确定PDIA 5是癌症中ATF 6 α介导的细胞功能的关键调节因子。
ATF6 alpha, 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 alpha 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 alpha in chemoresistance and defined the protein disulfide isomerase A5 (PDIA5) as necessary for ATF6 alpha activation upon ER stress. PDIA5 contributed to disulfide bond rearrangement in ATF6 alpha under stress conditions, thereby leading to ATF6 alpha export from the ER and activation of its target genes. Further analysis of the mechanism demonstrated that PDIA5 promotes ATF6 alpha packaging into coat protein complex II (COPII) vesicles and that the PDIA5/ATF6 alpha activation loop is essential to confer chemoresistance on cancer cells. Genetic and pharmacological inhibition of the PDIA5/ATF6 alpha axis restored sensitivity to the drug treatment. This work defines the mechanisms underlying the role of ATF6 alpha activation in carcinogenesis and chemoresistance; furthermore, it identifies PDIA5 as a key regulator ATF6 alpha-mediated cellular functions in cancer.