文献类型：期刊文献

中文题名：Smad5 acts as an intracellular pH messenger and maintains bioenergetic homeostasis

英文题名：Smad5 acts as an intracellular pH messenger and maintains bioenergetic homeostasis

作者：Yujiang Fang[1];Zhongliang Liu[1];Zhenyu Chen[1];Xiangjie Xu[1];Mengtao Xiao[4];Yanyan Yu[4];Yuanyuan Zhang[1];Xiaobai Zhang[3];Yanhua Du[3];Cizhong Jiang[3];Yuzheng Zhao[5];Yiran Wang[1];Beibei Fan[1];Daniel Terheyden-Keighley[1];Yang Liu[1];Lei Shi[1];Yi Hui[2];Xin Zhang[2];Bowen Zhang[1];Hexi Feng[1];Lin Ma[1];Quanbin Zhang[1];Guohua Jin[2];Yi Yang[5];Bin Xiang[4];Ling Liu[1,6];Xiaoqing Zhang[1,6,7]

机构：[1]Shanghai Tenth People's Hospital, and Neuroregeneration Key Laboratory of Shanghai Universities, Tongji University Schoolof Medicine, Shanghai 200092, China;[2]Department of Anatomy and Neurobiology, the Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China;[3]The School of Life Sciences and Technology, Tongji University,Shanghai 200092, China;[4]China Novartis Institutes for BioMedical Research, Shanghai 201203, China;[5]Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Bio-manufacturing Technology, East China University of Science and Technology, Shanghai 200237, China;[6]Tongji University Advanced Institute of Translational Medicine, Shanghai 200092, China;[7]The Collaborative Innovation Center for Brain Science,Tongji University, Shanghai 200092, China

年份：2017

卷号：27

期号：9

起止页码：1083

中文期刊名：Cell Research

外文期刊名：细胞研究（英文版）

收录：CSTPCD;;Scopus;CSCD:【CSCD2017_2018】；PubMed;

基金：We thank Xinhua Feng for offering Smad cDNAs. We thank Zhengliang Gao, Andong Qiu and Ying Cao for helpful dis- cussions. We also thank Margaret Ho for proof reading of the manuscript. This study was supported by the National Basic Research Program of China （2013CB967600）, Science and Tech- nology Commission of Shanghai Municipality （15JC 1400202, 15XD1503800）, National Natural Science Foundation of China （31471040, 31400934, 31225008, 31671484）, Ministry of Educa- tion （IRT1168） and Fundamental Research Funds for the Central Universities.

语种：英文

中文关键词：Smad5; intracellular pH; BMP; glycolysis; human pluripotent stem cells

外文关键词：能量平衡;细胞内;pH值;骨形态发生蛋白;细胞质基因;信号通路;代谢紊乱;发育过程

摘要：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.