Peroxidasin is a novel target of the redox-sensitive transcription factor Nrf2
Peroxidasin is a novel target of the redox-sensitive transcription factor Nrf2
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DOI：
10.1016/j.gene.2018.06.076
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发表时间：
2018-10-20
期刊：
影响因子：
3.5
通讯作者：
Mavri-Damelin, Demetra
中科院分区：
文献类型：
--
作者：
Hanmer, Kerry L.;Mavri-Damelin, Demetra
过氧化物酶（PXDN）通过利用过氧化氢（H2O2）促进过氧化反应，并已显示在次卤酸存在下通过硫亚胺键形成交联胶原蛋白IV。异常PXDN表达与肾纤维化、癌症、先天性眼缺陷和各种心血管疾病有关。由于PXDN的表达被H2O2修饰，我们假设一个主要的抗氧化反应转录因子，核因子红细胞2相关因子2（Nrf2），可以调节PXDN的表达。在HeLa和HEK293细胞中，通过蛋白质印迹法和免疫荧光显微镜法测定PXDN对H2O2和Nrf2特异性诱导剂叔丁基对苯二酚（tBHQ）和萝卜硫素（SFN）的表达。染色质免疫沉淀和荧光素酶报告基因分析用于研究Nrf2对PXDN的调控。在两种细胞系中，我们观察到H2O2、tBHQ和SFN引起的Nrf2核转位升高和PXDN蛋白表达增加。我们发现Nrf2通过推定的Nrf2结合位点结合并增加PXDN启动子的荧光素酶报告基因表达。总之，我们表明PXDN是氧化还原敏感性转录因子Nrf2的新靶点。这一发现进一步强调了PXDN在氧化还原相关过程中的作用，并补充了目前理解的PXDN的病理生理功能。
Peroxidasin (PXDN) facilitates peroxidative reactions via utilisation of hydrogen peroxide (H2O2) and has been shown to crosslink collagen IV through sulfilimine bond formation in the presence of hypohalous acids. Aberrant PXDN expression has been associated with kidney fibrosis, cancer, congenital eye defects and various cardiovascular disorders. Since PXDN expression is modified by H2O2, we hypothesized that a major antioxidant response transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), may regulate PXDN expression. PXDN expression in response to H2O2 and the Nrf2-specific inducers, tert-butylhydroquinone (tBHQ) and sulforaphane (SFN), was determined by western blotting and immunofluorescence microscopy, in HeLa and HEK293 cells. Chromatin immunoprecipitation and luciferase reporter assays were used to investigate the regulation of PXDN by Nrf2. We observed elevated Nrf2 nuclear translocation and increased PXDN protein expression in response to H2O2, tBHQ and SFN, in both cell lines. We found that Nrf2 binds to and increases luciferase reporter gene expression from the PXDN promoter via a putative Nrf2-binding site. In summary, we show that PXDN is a novel target of the redox sensitive transcription factor Nrf2. This finding further highlights the role of PXDN in redox-related processes and compliments the currently understood pathophysiological functions of PXDN.