Volume 27, No 9, Sep 2017

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 27 Issue 9, September 2017: 1083-1099   |  Open Access

ORIGINAL ARTICLES

Smad5 acts as an intracellular pH messenger and maintains bioenergetic homeostasis

Yujiang Fang¹, Zhongliang Liu¹, Zhenyu Chen¹, Xiangjie Xu¹, Mengtao Xiao⁴, Yanyan Yu⁴, Yuanyuan Zhang¹, Xiaobai Zhang³, Yanhua Du³, Cizhong Jiang³, Yuzheng Zhao⁵, Yiran Wang¹, Beibei Fan¹, Daniel Terheyden-Keighley¹, Yang Liu¹, Lei Shi¹, Yi Hui², Xin Zhang², Bowen Zhang¹, Hexi Feng¹, Lin Ma¹, Quanbin Zhang¹, Guohua Jin², Yi Yang⁵, Bin Xiang⁴, Ling Liu^1,6 and Xiaoqing Zhang^1,6,7

¹Shanghai Tenth People's Hospital, and Neuroregeneration Key Laboratory of Shanghai Universities, Tongji University School of Medicine, Shanghai 200092, China
²Department of Anatomy and Neurobiology, the Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Jiangsu 226001, China
³The School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
⁴China Novartis Institutes for BioMedical Research, Shanghai 201203, China
⁵Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, Shanghai 200237, China
⁶Tongji University Advanced Institute of Translational Medicine, Shanghai 200092, China
⁷The Collaborative Innovation Center for Brain Science, Tongji University, Shanghai 200092, China Correspondence: Xiaoqing Zhang, Tel: 86-21-65982435; Fax: 86-21-65985003 E-mail: xqzhang@tongji.edu.cn; Ling Liu, Tel: 86-21-65985003; Fax: 86-21-65985003 Email: lliu@tongji.edu.cn; Bin Xiang,(bin.xiang@novartis.com)

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.

10.1038/cr.2017.85

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