Maisonneuve-Rosemont Hospital, Research Center, Université de Montréal, Department of Medicine, 5415 Boul. de l' Assomption, Montréal, Québec, H1T 2M4, Canada.
Segal Cancer Centre and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote Ste-Catherine Road, Montréal, Québec, H3T 1E2, Canada.
Sci Rep. 2016 Jul 8;6:29389. doi: 10.1038/srep29389.
APE1 is an essential DNA repair protein that also possesses the ability to regulate transcription. It has a unique cysteine residue C65, which maintains the reduce state of several transcriptional activators such as NF-κB. How APE1 is being recruited to execute the various biological functions remains unknown. Herein, we show that APE1 interacts with a novel partner PRDX1, a peroxidase that can also prevent oxidative damage to proteins by serving as a chaperone. PRDX1 knockdown did not interfere with APE1 expression level or its DNA repair activities. However, PRDX1 knockdown greatly facilitates APE1 detection within the nucleus by indirect immunofluorescence analysis, even though APE1 level was unchanged. The loss of APE1 interaction with PRDX1 promotes APE1 redox function to activate binding of the transcription factor NF-κB onto the promoter of a target gene, the proinflammatory chemokine IL-8 involved in cancer invasion and metastasis, resulting in its upregulation. Depletion of APE1 blocked the upregulation of IL-8 in the PRDX1 knockdown cells. Our findings suggest that the interaction of PRDX1 with APE1 represents a novel anti-inflammatory function of PRDX1, whereby the association safeguards APE1 from reducing transcription factors and activating superfluous gene expression, which otherwise could trigger cancer invasion and metastasis.
APE1 是一种必需的 DNA 修复蛋白，它还具有调节转录的能力。它具有独特的半胱氨酸残基 C65，可维持几种转录激活因子（如 NF-κB）的还原状态。APE1 如何被招募来执行各种生物学功能仍不清楚。在此，我们表明 APE1 与一种新的伴侣 PRDX1 相互作用，PRDX1 是一种过氧化物酶，也可以作为伴侣蛋白防止蛋白质发生氧化损伤。PRDX1 的敲低并不干扰 APE1 的表达水平或其 DNA 修复活性。然而，通过间接免疫荧光分析，PRDX1 的敲低大大促进了核内 APE1 的检测，尽管 APE1 水平没有变化。APE1 与 PRDX1 相互作用的丧失促进了 APE1 的氧化还原功能，激活转录因子 NF-κB 与靶基因启动子的结合，该靶基因是参与癌症侵袭和转移的促炎趋化因子 IL-8，从而导致其上调。APE1 的耗竭阻止了 PRDX1 敲低细胞中 IL-8 的上调。我们的研究结果表明，PRDX1 与 APE1 的相互作用代表了 PRDX1 的一种新的抗炎功能，通过这种关联，APE1 免受还原转录因子和激活多余基因表达的影响，否则可能引发癌症侵袭和转移。
