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首页> 外文期刊>American Journal of Physiology >tert-Butylhydroquinone mobilizes intracellular-bound zinc to stabilize Nrf2 through inhibiting phosphatase activity
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tert-Butylhydroquinone mobilizes intracellular-bound zinc to stabilize Nrf2 through inhibiting phosphatase activity

机译：叔丁基氢醌通过抑制磷酸酶活性来动员细胞内结合的锌以稳定NRF2

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摘要

The nuclear factor erythroid 2-related factor 2 (Nrf2) is required to combat increases in oxidative stress. The chemical compound te/t-butylhydroquinone (tBHQ) can downregulate Kelch-like ECH-associated protein 1 (Keapl), arepres-sor of Nrf2, thus maintaining the stability of Nrf2. tBHQ can also increase intracellular "free" zinc in human bronchial epithelial (16HBE) cells. We aim to investigate whether the intracellular free zinc change plays a role in Nrf2 activation. tBHQ exposure dose-dependently increases intracellular free zinc concentrations within 30 min in 16HBE cells by mobilizing intracellular zinc pools. Active Nrf2 and the antioxidant enzyme heme oxygenase-1 (HO-1) increase at 3 h after tBHQ treatment. Chelating intracellular free zinc with tetrakis-(2-pyridylmethyl)ethylenediamine (TPEN) during tBHQ exposure partially abrogates the tBHQ-induced activation of Nrf2 and HO-1 expression, while Keapl is further decreased. These results indicate that tBHQ-induced stability of Nrf2 is associated with the intracellular free zinc level. Because the activated Nrf2 is phosphor-ylated, the serine/threonine protein phosphatase activity, which is known to be inhibited by zinc, is assayed. The results showed that tBHQ treatment can suppress cellular protein phosphatase-2A (PP2A) and protein phosphatase-2C (PP2C) activity, which can be abrogated by adding TPEN. This finding is verified in a cell-free protein extract experiment by supplying zinc or by chelating zinc with TPEN. These results provide a novel mechanistic insight into Nrf2 activation in antioxidant enzyme induction involving zinc signaling. The increase of intracellular free zinc may be one mechanism for Nrf2 activation. The inhibition of PP2A and PP2C activity may be involved in Nrf2 phosphorylation modulation.
机译：核因子红外2相关因子2（NRF2）需要对抗氧化应激的增加。化学化合物TE / T-叔丁基羟基醌（TBHQ）可以下调keelch样的ech-相关蛋白1（Keapl），NRF2的含量吸附，从而保持NRF2的稳定性。 TBHQ还可以在人支气管上皮（16HBE）细胞中增加细胞内的“自由”锌。我们的目的是探讨细胞内自由锌改变是否在NRF2激活中发挥作用。通过动员细胞内锌池，TBHQ暴露剂量依赖于16HBE细胞内30分钟内增加细胞内游离锌浓度。活性NRF2和抗氧化酶血红素酶-1（HO-1）在TBHQ处理后3小时增加。在TBHQ曝光期间用四甲基（2-吡啶甲基）乙二胺（TPEN）螯合细胞内游离锌部分废除了TBHQ诱导的NRF2和HO-1表达的活化，而KEAPL进一步降低。这些结果表明，TBHQ诱导的NRF2的稳定性与细胞内游离锌水平有关。因为活化的NRF 2是磷光体 - YLAX，所以通过锌抑制的丝氨酸/苏氨酸蛋白磷酸酶活性进行测定。结果表明，TBHQ治疗可以抑制细胞蛋白磷酸酶-2A（PP2A）和蛋白质磷酸酶-2C（PP2C）活性，这可以通过添加TPEN消除。通过供应锌或用TPEN螯合锌，在无细胞蛋白质提取物实验中验证了该发现。这些结果为涉及锌信号诱导的抗氧化酶诱导中的NRF2活化提供了一种新的机制洞察力。细胞内游离锌的增加可以是NRF2活化的一种机制。 PP2A和PP2C活性的抑制可参与NRF2磷酸化调节。

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