Nitric oxide controls nuclear export of APE1/Ref-1 through S-nitrosation of cysteines 93 and 310.
Nitric oxide controls nuclear export of APE1/Ref-1 through S-nitrosation of cysteines 93 and 310.
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DOI：
10.1093/nar/gkl1163
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发表时间：
2007
影响因子：
14.9
通讯作者：
Chen C
中科院分区：
文献类型：
--
作者：
Qu J;Liu GH;Huang B;Chen C
脱嘌呤/脱嘧啶核酸内切酶1/氧化还原效应因子-1（Apurinic/apyrimidinic endonuclease 1/redox effector factor-1，APE 1/Ref-1）是一类具有DNA修复和氧化还原调节双重功能的转录因子。大量的研究表明APE 1的生物活性对氧化应激敏感，但APE 1的功能是否受亚硝化应激的调控尚不清楚。在这项研究中，我们发现，S-亚硝基谷胱甘肽（GSNO），一氧化氮供体，也是一种S-亚硝基化剂，有效地刺激APE 1的核输出的CRM 1独立的方式。这种核质易位依赖于APE 1的S-亚硝化修饰，因为S-亚硝化靶位点Cys 93和Cys 310的同时突变完全废除了胞质再分布。该转运过程是可逆的和特异的，因为它可以被还原剂逆转，但不能被H2 O2模拟。在结构上，靠近Cys 93和Cys 310的区域aa.64-80和β链aa.311-316对于GSNO诱导的APE 1重新定位是重要的。此外，在NO损伤的细胞中发现了导入蛋白介导的核输入途径的缺陷，并鉴定了p50和HDAC 2为APE 1核输出抑制蛋白。总之，这项研究可能提供一种新的分子机制，将亚硝化应激与APE 1相关的生理和病理过程联系起来。
Apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/Ref-1, abbreviated as APE1) is a molecule with dual functions in DNA repair and redox regulation of transcription factors. Accumulated work has shown that the biological activities of APE1 are sensitive to oxidative stress; however, whether APE1 functions can be regulated by nitrosative stress remains unknown. In this investigation, we found that S-nitrosoglutathion (GSNO), a nitric oxide donor and also an S-nitrosating agent, effectively stimulated nuclear export of APE1 in a CRM1-independent manner. This nuclear-cytoplasmic translocation was dependent on S-nitrosation modification of APE1, as simultaneous mutation of S-nitrosation target sites Cys93 and Cys310 completely abrogated the cytoplasmic redistribution. The translocation process was reversal and specific, as it could be reversed by reductive reagents, but could not be mimicked by H2O2. In structure, the region aa.64–80 and the beta-strand aa.311–316 in proximity to Cys93 and Cys310 were important for GSNO-induced APE1 relocalization. In addition, a defect of importin-mediated nuclear import pathway was found in the NO-insulted cells, and p50 and HDAC2 were identified as APE1 nuclear export inhibitory proteins. Together, this study may provide a novel molecular mechanism, which links nitrosative stress to APE1-associated physiological and pathological processes.
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