title: Nucleoporin 35 regulates cardiomyocyte pH homeostasis by controlling Na+-H+ exchanger-1 expression.
abstract: The mammalian nuclear pore complex is comprised of ∼ 30 different nucleoporins (Nups). It governs the nuclear import of gene expression modulators and the export of mRNAs. In cardiomyocytes, Na(+)-H(+) exchanger-1 (NHE1) is an integral membrane protein that exclusively regulates intracellular pH (pHi) by exchanging one intracellular H(+) for one extracellular Na(+). However, the role of Nups in cardiac NHE1 expression remains unknown. We herein report that Nup35 regulates cardiomyocyte NHE1 expression by controlling the nucleo-cytoplasmic trafficking of nhe1 mRNA. The N-terminal domain of Nup35 determines nhe1 mRNA nuclear export by targeting the 5'-UTR (-412 to -213 nt) of nhe1 mRNA. Nup35 ablation weakens the resistance of cardiomyocytes to an acid challenge by depressing NHE1 expression. Moreover, we identify that Nup35 and NHE1 are simultaneously downregulated in ischemic cardiomyocytes both in vivo and in vitro. Enforced expression of Nup35 effectively counteracts the anoxia-induced intracellular acidification. We conclude that Nup35 selectively regulates cardiomyocyte pHi homeostasis by posttranscriptionally controlling NHE1 expression. This finding reveals a novel regulatory mechanism of cardiomyocyte pHi, and may provide insight into the therapeutic strategy for ischemic cardiac diseases.
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Institute of Medical Genetics, Tongji University, Shanghai 200092, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Pan
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Institute of Medical Genetics, Tongji University, Shanghai 200092, China Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Bijun
authors.initials: B
authors.lastname: Huang
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Feng
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Changming
authors.initials: C
authors.lastname: Li
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Shiyi
authors.initials: S
authors.lastname: Wang
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Erlinda
authors.initials: E
authors.lastname: The
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Institute of Medical Genetics, Tongji University, Shanghai 200092, China.
authors.forename: Tianyou
authors.initials: T
authors.lastname: Yuan
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Lixiao
authors.initials: L
authors.lastname: Zhen
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Institute of Medical Genetics, Tongji University, Shanghai 200092, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Liang
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Institute of Medical Genetics, Tongji University, Shanghai 200092, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Institute of Medical Genetics, Tongji University, Shanghai 200092, China Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Institute of Medical Genetics, Tongji University, Shanghai 200092, China Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China.
authors.forename: Yingyu
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Institute of Medical Genetics, Tongji University, Shanghai 200092, China Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Institute of Medical Genetics, Tongji University, Shanghai 200092, China Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China.
authors.forename: Luying
authors.initials: L
authors.lastname: Peng
authors.affiliation: Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Institute of Medical Genetics, Tongji University, Shanghai 200092, China Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China yihanchen@tongji.edu.cn yihanchen@hotmail.com.
authors.forename: Yi-Han
authors.initials: YH
authors.lastname: Chen
mesh_terms: D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D017404:In Situ Hybridization, Fluorescence; D032383:Myocytes, Cardiac / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers
keywords: Na+-H+ exchanger; cardiomyocyte; intracellular pH; nuclear pore complex; nucleo-cytoplasmic transport