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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Aquaporin-3 mediates hydrogen peroxide uptake to regulate downstream intracellular signaling
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Aquaporin-3 mediates hydrogen peroxide uptake to regulate downstream intracellular signaling

机译：Aquaporin-3介导过氧化氢的吸收以调节下游细胞内信号传导

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摘要

Hydrogen peroxide (H_2O_2) produced by cell-surface NADPH Oxi-dase (Nox) enzymes is emerging as an important signaling molecule for growth, differentiation, and migration processes. However, how cells spatially regulate H_2O_2. to achieve physiological redox signaling over nonspecific oxidative stress pathways is insufficiently understood. Here we report that the water channel Aquaporin-3 (AQP3) can facilitate the uptake of H_2O_2 into mammalian cells and mediate downstream intracellular signaling. Molecular imaging with Peroxy Yellow 1 Methyl-Ester (PY1-ME), a new che-moselective fluorescent indicator for H_2O_2, directly demonstrates that aquaporin isoforms AQP3 and AQP8, but not AQP1, can promote uptake of H_2O_2 specifically through membranes in mammalian cells. Moreover, we show that intracellular H_2O_2 accumulation can be modulated up or down based on endogenous AQP3 expression, which in turn can influence downstream cell signaling cascades. Finally, we establish that AQP3 is required for Nox-derived H_2O_2 signaling upon growth factor stimulation. Taken together, our findings demonstrate that the downstream intracellular effects of H_2O_2 can be regulated across biological barriers, a discovery that has broad implications for the controlled use of this potentially toxic small molecule for beneficial physiological functions.
机译：细胞表面NADPH氧化酶（Nox）酶产生的过氧化氢（H_2O_2）逐渐成为重要的信号分子，用于生长，分化和迁移过程。但是，细胞如何在空间上调节H_2O_2。在非特异性氧化应激途径上实现生理氧化还原信号的认识还不够充分。在这里，我们报告水通道Aquaporin-3（AQP3）可以促进H_2O_2进入哺乳动物细胞并介导下游细胞内信号传导。使用过氧黄1甲基酯（PY1-ME）进行的分子成像是一种针对H_2O_2的新型化学选择性荧光指示剂，直接表明水通道蛋白同工型AQP3和AQP8而非AQP1可以促进H_2O_2的吸收，特别是通过哺乳动物细胞膜的吸收。此外，我们表明细胞内H_2O_2积累可以基于内源性AQP3表达而被向上或向下调节，这反过来又可以影响下游细胞信号级联反应。最后，我们确定生长因子刺激后，Nox衍生的H_2O_2信号传导需要AQP3。综上所述，我们的发现表明H_2O_2的下游细胞内作用可通过生物屏障进行调节，这一发现对这种潜在有毒的小分子对有益生理功能的控制使用具有广泛的意义。

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