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Inhibiting MARSs reduces hyperhomocysteinemia-associated neural tube and congenital heart defects.

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收录情况： ◇ SCIE

作者：
Mei Xinyu[1,2,3,4] ; Qi Dashi[1,5] ; Zhang Ting[1,6] ; Zhao Ying[1,2,7] ; Jin Li[1,2] ; Hou Junli[8] ; Wang Jianhua[6] ; Lin Yan[1,2,4] ; Xue Yu[9] ; Zhu Pingping[8] ; Liu Zexian[9] ; Huang Lei[1,2] ; Nie Ji[1,2] ; Si Wen[8] ; Ma Jingyi[10] ; Ye Jianhong[1,2] ; Finnell Richard H[11] ; Saiyin Hexige[1] ; Wang Hongyan[1,2] ; Zhao Jianyuan[1,2,4] ; Zhao Shimin[1,2,4] ; Xu Wei[1,2,4] ;
机构： [1]State Key Lab of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Obstetrics & Gynecology Hospital of Fudan University, Shanghai, China [2]NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai, China [3]Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China [4]Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China [5]Shanghai Key Lab of Birth Defect, Children’s Hospital of Fudan University, Shanghai, China [6]Capital Institute of Pediatrics, Beijing, China [7]Shanghai Laboratory Animal Research Center, Shanghai, China [8]Department of Chemistry, Fudan University, Shanghai, China [9]Department of Medical Engineering, College of Life Sciences and Technology, Huazhong University of Science and Technology, Wuhan, China [10]Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK [11]Center for Precision Environmental Health, Departments of Molecular and Human Genetics, Molecular & Cellular Biology and Medicine, Baylor College of Medicine,Houston, TX, USA
出处：
DOI： 10.15252/emmm.201809469
ISSN：

关键词： acetyl homocysteine thioether methionyl-tRNA synthetase neural tube defects N-homocysteinylation reactive oxygen species

摘要：
Hyperhomocysteinemia is a common metabolic disorder that imposes major adverse health consequences. Reducing homocysteine levels, however, is not always effective against hyperhomocysteinemia-associated pathologies. Herein, we report the potential roles of methionyl-tRNA synthetase (MARS)-generated homocysteine signals in neural tube defects (NTDs) and congenital heart defects (CHDs). Increased copy numbers of MARS and/or MARS2 were detected in NTD and CHD patients. MARSs sense homocysteine and transmit its signal by inducing protein lysine (N)-homocysteinylation. Here, we identified hundreds of novel N-homocysteinylated proteins. N-homocysteinylation of superoxide dismutases (SOD1/2) provided new mechanistic insights for homocysteine-induced oxidative stress, apoptosis and Wnt signalling deregulation. Elevated MARS expression in developing and proliferating cells sensitizes them to the effects of homocysteine. Targeting MARSs using the homocysteine analogue acetyl homocysteine thioether (AHT) reversed MARS efficacy. AHT lowered NTD and CHD onsets in retinoic acid-induced and hyperhomocysteinemia-induced animal models without affecting homocysteine levels. We provide genetic and biochemical evidence to show that MARSs are previously overlooked genetic determinants and key pathological factors of hyperhomocysteinemia, and suggest that MARS inhibition represents an important medicinal approach for controlling hyperhomocysteinemia-associated diseases. © 2020 The Authors. Published under the terms of the CC BY 4.0 license.

基金：
State Key Development Programs of China [2018YFA0801300, 2018YFC1004700, 2018YFA0800300]; National Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31330023, 81722021, 31671483, 81771627, 31521003, 31821002, 91753207, 31930062, 31871432, 81974175, 81500977, U1432242, 31425008, 31801167]; Science and Technology Municipal Commission of Shanghai, China [16JC1405300, 17YF1424200]; Shanghai Rising-Star Program [18QA1400300]; Shanghai Medical Center of Key Programs for Female Reproduction Diseases [2017ZZ01016]; Key Laboratory of Reproduction Regulation of NPFPC
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外文
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PubmedID：
中科院(CAS)分区：
出版当年[2020]版：
大类 | 1 区 医学
小类 | 1 区 医学：研究与实验
最新[2023]版：
大类 | 1 区 医学
小类 | 1 区 医学：研究与实验
JCR分区：
出版当年[2020]版：
Q1 MEDICINE, RESEARCH & EXPERIMENTAL
最新[2023]版：
Q1 MEDICINE, RESEARCH & EXPERIMENTAL

影响因子： 最新[2023版] 最新五年平均 出版当年[2020版] 出版当年五年平均 出版前一年[2019版] 出版后一年[2021版]

第一作者：
第一作者机构： [1]State Key Lab of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Obstetrics & Gynecology Hospital of Fudan University, Shanghai, China [2]NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai, China [3]Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China [4]Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
共同第一作者：
通讯作者：
通讯机构： [1]State Key Lab of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Obstetrics & Gynecology Hospital of Fudan University, Shanghai, China [2]NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai, China [4]Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
推荐引用方式(GB/T 7714)：
Mei Xinyu,Qi Dashi,Zhang Ting,et al.Inhibiting MARSs reduces hyperhomocysteinemia-associated neural tube and congenital heart defects.[J].EMBO MOLECULAR MEDICINE.2020,12(3):doi:10.15252/emmm.201809469.
APA：
Mei Xinyu,Qi Dashi,Zhang Ting,Zhao Ying,Jin Li...&Xu Wei.(2020).Inhibiting MARSs reduces hyperhomocysteinemia-associated neural tube and congenital heart defects..EMBO MOLECULAR MEDICINE,12,(3)
MLA：
Mei Xinyu,et al."Inhibiting MARSs reduces hyperhomocysteinemia-associated neural tube and congenital heart defects.".EMBO MOLECULAR MEDICINE 12..3(2020)

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