Uterine FK506-binding protein 52 (FKBP52)-peroxiredoxin-6 (PRDX6) signaling protects pregnancy from overt oxidative stress
Uterine FK506-binding protein 52 (FKBP52)-peroxiredoxin-6 (PRDX6) signaling protects pregnancy from overt oxidative stress
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DOI：
10.1073/pnas.1009324107
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发表时间：
2010-08-31
影响因子：
11.1
通讯作者：
Dey, Sudhansu K.
中科院分区：
文献类型：
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作者：
Hirota, Yasushi;Acar, Nuray;Dey, Sudhansu K.
亲免疫蛋白fk506结合蛋白52 （FKBP52）是一种与黄体酮受体（PR）结合以优化黄体酮(P-4)-PR信号传导的辅伴侣。我们最近发现，Fkbp52缺陷（Fkbp52(-/-)）小鼠的子宫PR反应性降低，着床失败，这是通过过量补充P-4以遗传背景依赖的方式挽救的。这一发现使我们假设FKBP52除了优化PR活性外还有其他功能。通过蛋白质组学分析，我们发现Fkbp52（-/-）小鼠子宫中过氧化氧还蛋白-6 （PRDX6）的水平明显低于WT和PR-null （Pgr(-/-)）小鼠。我们还发现，子宫PRDX6水平降低的Fkbp52（-/-）小鼠容易受到百草枯诱导的氧化应激（OS）的影响，即使补充P-4也会导致着床失败。相同剂量的百草枯对WT小鼠的着床没有影响。此外，抗氧化剂α -生育酚和n -乙酰半胱氨酸（NAC）可减轻百草枯诱导的Fkbp52（-/-）小鼠着床失败。对小鼠胚胎成纤维细胞的功能分析表明，Fkbp52缺陷与PRDX6水平降低相关，可促进h2o2诱导的细胞死亡，而添加NAC或强迫PRDX6表达可逆转这一过程，这表明Fkbp52缺陷通过降低PRDX6水平降低OS的阈值。这些发现提供了证据，在PRDX6水平降低的Fkbp52（-/-）女性中，子宫OS升高即使在P-4过量的情况下也会导致植入失败。本研究表明FKBP52-PRDX6信号可以保护妊娠免受显性OS的影响。
Immunophilin FK506-binding protein 52 (FKBP52) is a cochaperone that binds to the progesterone receptor (PR) to optimize progesterone (P-4)-PR signaling. We recently showed that Fkbp52-deficient (Fkbp52(-/-)) mice have reduced uterine PR responsiveness and implantation failure which is rescued by excess P-4 supplementation in a genetic background-dependent manner. This finding led us to hypothesize that FKBP52 has functions in addition to optimizing PR activity. Using proteomics analysis, we found that uterine levels of peroxiredoxin-6 (PRDX6), a unique antioxidant, are significantly lower in Fkbp52(-/-) mice than in WT and PR-null (Pgr(-/-)) mice. We also found that Fkbp52(-/-) mice with reduced uterine PRDX6 levels are susceptible to paraquat-induced oxidative stress (OS), leading to implantation failure even with P-4 supplementation. The same dose of paraquat did not interfere with implantation in WT mice. Moreover, treatment with antioxidants alpha-tocopherol and N-acetylcysteine (NAC) attenuated paraquat-induced implantation failure in P-4-treated Fkbp52(-/-) mice. Functional analyses using mouse embryonic fibroblasts show that Fkbp52 deficiency associated with reduced PRDX6 levels promotes H2O2-induced cell death, which is reversed by the addition of NAC or by forced expression of PRDX6, suggesting that Fkbp52 deficiency diminishes the threshold against OS by reducing PRDX6 levels. These findings provide evidence that heightened uterine OS in Fkbp52(-/-) females with reduced PRDX6 levels induces implantation failure even in the presence of excess P-4. This study shows that FKBP52-PRDX6 signaling protects pregnancy from overt OS.