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Smad5 acts as an intracellular pH messenger and maintains bioenergetic homeostasis
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Smad5 acts as an intracellular pH messenger and maintains bioenergetic homeostasis
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Journal Article
Smad5 acts as an intracellular pH messenger and maintains bioenergetic homeostasis
2017
Overview
Both environmental cues and intracellular bioenergetic states profoundly affect intraceUular 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 SmadS, 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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Ablation
/ Active Transport, Cell Nucleus
/ Biomedical and Life Sciences
/ Bone Morphogenetic Proteins - metabolism
/ Human Embryonic Stem Cells - cytology
/ Human Embryonic Stem Cells - metabolism
/ Human Embryonic Stem Cells - ultrastructure
/ Humans
/ Intracellular Space - metabolism
/ Original
/ pH值
/ Protons
/ Receptors, Cytoplasmic and Nuclear - metabolism
/ Structure-Activity Relationship
/ 代谢紊乱
/ 信号通路
/ 发育过程
/ 细胞内
/ 细胞质基因
/ 能量平衡
/ 骨形态发生蛋白
