Inhibiting MARSs reduces hyperhomocysteinemia-associated neural tube and congenital heart defects.,EMBO Molecular Medicine

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Inhibiting MARSs reduces hyperhomocysteinemia-associated neural tube and congenital heart defects.
EMBO Molecular Medicine ( IF 9.0 ) Pub Date : 2020-01-31 , DOI: 10.15252/emmm.201809469
Xinyu Mei _{1,

2,

3,

4} , Dashi Qi _{1,

5} , Ting Zhang _{1,

6} , Ying Zhao _{1,

2,

7} , Li Jin _{1,

2} , Junli Hou ₈ , Jianhua Wang ₆ , Yan Lin _{1,

2,

4} , Yu Xue ₉ , Pingping Zhu ₈ , Zexian Liu ₉ , Lei Huang _{1,

2} , Ji Nie _{1,

2} , Wen Si ₈ , Jingyi Ma ₁₀ , Jianhong Ye _{1,

2} , Richard H Finnell ₁₁ , Hexige Saiyin ₁ , Hongyan Wang _{1,

2} , Jianyuan Zhao _{1,

2,

4} , Shimin Zhao _{1,

2,

4} , Wei Xu _{1,

2,

4}

Affiliation

State Key Lab of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Obstetrics & Gynecology Hospital of Fudan University, Shanghai, China.
NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai, China.
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China.
Capital Institute of Pediatrics, Beijing, China.
Shanghai Laboratory Animal Research Center, Shanghai, China.
Department of Chemistry, Fudan University, Shanghai, China.
Department of Medical Engineering, College of Life Sciences and Technology, Huazhong University of Science and Technology, Wuhan, China.
Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
Center for Precision Environmental Health, Departments of Molecular and Human Genetics, Molecular & Cellular Biology and Medicine, Baylor College of Medicine, Houston, TX, USA.

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.

中文翻译：

抑制 MARS 可减少与高同型半胱氨酸血症相关的神经管和先天性心脏缺陷。

高同型半胱氨酸血症是一种常见的代谢性疾病，会造成严重的健康不良后果。然而，降低同型半胱氨酸水平并不总是能有效对抗高同型半胱氨酸血症相关的病症。在此，我们报告了甲硫氨酰-tRNA 合成酶 (MARS) 产生的同型半胱氨酸信号在神经管缺陷 (NTD) 和先天性心脏缺陷 (CHD) 中的潜在作用。在 NTD 和 CHD 患者中检测到 MARS 和/或 MARS2 拷贝数增加。 MARS 感知同型半胱氨酸并通过诱导蛋白质赖氨酸 (N)-同型半胱氨酸化来传输其信号。在这里，我们鉴定了数百种新型 N-同型半胱氨酸化蛋白。超氧化物歧化酶 (SOD1/2) 的 N-同型半胱氨酸化为同型半胱氨酸诱导的氧化应激、细胞凋亡和 Wnt 信号转导失调提供了新的机制见解。发育和增殖细胞中 MARS 表达升高使它们对同型半胱氨酸的作用敏感。使用同型半胱氨酸类似物乙酰同型半胱氨酸硫醚 (AHT) 靶向 MARS 可逆转 MARS 功效。 AHT 降低了视黄酸诱导和高同型半胱氨酸血症诱导的动物模型中 NTD 和 CHD 的发病率，且不影响同型半胱氨酸水平。我们提供的遗传和生化证据表明，MARS 是以前被忽视的高同型半胱氨酸血症的遗传决定因素和关键病理因素，并表明 MARS 抑制代表了控制高同型半胱氨酸血症相关疾病的重要医学方法。

更新日期：2020-03-06

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