Okamoto Shu-Ichi, Nakamura Tomohiro, Cieplak Piotr, Chan Shing Fai, Kalashnikova Evgenia, Liao Lujian, Saleem Sofiyan, Han Xuemei, Clemente Arjay, Nutter Anthony, Sances Sam, Brechtel Christopher, Haus Daniel, Haun Florian, Sanz-Blasco Sara, Huang Xiayu, Li Hao, Zaremba Jeffrey D, Cui Jiankun, Gu Zezong, Nikzad Rana, Harrop Anne, McKercher Scott R, Godzik Adam, Yates John R, Lipton Stuart A
Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cell Rep. 2014 Jul 10;8(1):217-28. doi: 10.1016/j.celrep.2014.06.005. Epub 2014 Jul 4.
Redox-mediated posttranslational modifications represent a molecular switch that controls major mechanisms of cell function. Nitric oxide (NO) can mediate redox reactions via S-nitrosylation, representing transfer of an NO group to a critical protein thiol. NO is known to modulate neurogenesis and neuronal survival in various brain regions in disparate neurodegenerative conditions. However, a unifying molecular mechanism linking these phenomena remains unknown. Here, we report that S-nitrosylation of myocyte enhancer factor 2 (MEF2) transcription factors acts as a redox switch to inhibit both neurogenesis and neuronal survival. Structure-based analysis reveals that MEF2 dimerization creates a pocket, facilitating S-nitrosylation at an evolutionally conserved cysteine residue in the DNA binding domain. S-Nitrosylation disrupts MEF2-DNA binding and transcriptional activity, leading to impaired neurogenesis and survival in vitro and in vivo. Our data define a molecular switch whereby redox-mediated posttranslational modification controls both neurogenesis and neurodegeneration via a single transcriptional signaling cascade.
氧化还原介导的翻译后修饰代表一种控制细胞功能主要机制的分子开关。一氧化氮（NO）可通过S-亚硝基化介导氧化还原反应，即NO基团转移至关键蛋白质硫醇。已知NO在不同神经退行性疾病中可调节各个脑区的神经发生和神经元存活。然而，连接这些现象的统一分子机制仍不清楚。在此，我们报道肌细胞增强因子2（MEF2）转录因子的S-亚硝基化作为一种氧化还原开关，可抑制神经发生和神经元存活。基于结构的分析表明，MEF2二聚化形成一个口袋，便于在DNA结合域中一个进化保守的半胱氨酸残基处发生S-亚硝基化。S-亚硝基化破坏MEF2与DNA的结合及转录活性，导致体外和体内神经发生及存活受损。我们的数据定义了一种分子开关，通过该开关氧化还原介导的翻译后修饰可通过单一转录信号级联控制神经发生和神经退行性变。
