Smad5 acts as an intracellular pH messenger and maintains bioenergetic homeostasis.
Smad5 acts as an intracellular pH messenger and maintains bioenergetic homeostasis.
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Smad5 作为细胞内 pH 信使并维持生物能稳态
DOI：
10.1038/cr.2017.85
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发表时间：
2017-09
期刊：
影响因子：
44.1
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Fang Y;Liu Z;Chen Z;Xu X;Xiao M;Yu Y;Zhang Y;Zhang X;Du Y;Jiang C;Zhao Y;Wang Y;Fan B;Terheyden-Keighley D;Liu Y;Shi L;Hui Y;Zhang X;Zhang B;Feng H;Ma L;Zhang Q;Jin G;Yang Y;Xiang B;Liu L;Zhang X
环境因素和细胞内生物能状态都深刻地影响细胞内pH（pHi）。细胞如何响应pHi变化以维持生物能稳态仍然是难以捉摸的。在这里，我们表明，Smad5，骨形态发生蛋白（BMP）信号传导的一个良好的特征下游组件响应pHi的变化。冷，碱性或高渗条件下增加pHi，这反过来又解离质子从带电荷的氨基酸簇内的MH1结构域的Smad5，促使其从细胞核的搬迁到细胞质。另一方面，热、酸性或低渗条件降低pHi，阻断Smad5的核输出，从而导致其核积累。环境变化和pHi波动诱导的Smad5的核质穿梭活性独立于BMP信号、羧基端磷酸化和Smad4。此外，Smad5的消融导致细胞生物能量稳态的慢性和不可逆的失调，并破坏正常的神经发育过程，如在人多能干细胞的分化模型中所鉴定的。重要的是，Smad5缺陷细胞中的这些代谢和发育缺陷只能通过细胞质Smad5来挽救。细胞质Smad5与己糖激酶1物理相互作用并加速糖酵解。总之，我们的研究结果表明，Smad5作为一个pHi信使，并通过调节细胞质代谢机制维持细胞的生物能量稳态。
Both environmental cues and intracellular bioenergetic states profoundly affect intracellular pH (pHi). How a cell responds to pHi changes to maintain bioenergetic homeostasis remains elusive. Here we show that Smad5, a well-characterized downstream component of bone morphogenetic protein (BMP) signaling responds to pHi changes. Cold, basic or hypertonic conditions increase pHi, which in turn dissociates protons from the charged amino acid clusters within the MH1 domain of Smad5, prompting its relocation from the nucleus to the cytoplasm. On the other hand, heat, acidic or hypotonic conditions decrease pHi, blocking the nuclear export of Smad5, and thus causing its nuclear accumulation. Active nucleocytoplasmic shuttling of Smad5 induced by environmental changes and pHi fluctuation is independent of BMP signaling, carboxyl terminus phosphorylation and Smad4. In addition, ablation of Smad5 causes chronic and irreversible dysregulation of cellular bioenergetic homeostasis and disrupted normal neural developmental processes as identified in a differentiation model of human pluripotent stem cells. Importantly, these metabolic and developmental deficits in Smad5-deficient cells could be rescued only by cytoplasmic Smad5. Cytoplasmic Smad5 physically interacts with hexokinase 1 and accelerates glycolysis. Together, our findings indicate that Smad5 acts as a pHi messenger and maintains the bioenergetic homeostasis of cells by regulating cytoplasmic metabolic machinery.
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