S-Nitrosylation-Mediated Redox Transcriptional Switch Modulates Neurogenesis and Neuronal Cell Death

• Published in: Cell reports (Cambridge) 2014-07, Vol.8 (1), p.217-228
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Binding Sites; Cells, Cultured; DNA - metabolism; HEK293 Cells; Humans; MEF2 Transcription Factors - chemistry; MEF2 Transcription Factors - genetics; MEF2 Transcription Factors - metabolism; Mice; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; Neurogenesis; Nitric Oxide - metabolism; Oxidation-Reduction; Protein Binding; Protein Processing, Post-Translational; Transcriptional Activation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.06.005

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. [Display omitted] •S-Nitrosylation of MEF2 at conserved cysteine residues occurs in plants and animal•S-Nitrosylation of MEF2 inhibits its DNA binding and transcriptional activity•S-Nitrosylation of MEF2 inhibits both neurogenesis and neuronal survival S-Nitrosylation represents a posttranslational modification (PTM) of cysteine thiol by nitric oxide species. This redox-mediated PTM is critical for regulating protein function, comparable to other PTMs such as phosphorylation or acetylation. In this study, Okamoto et al. show that a single S-nitrosylation reaction on an evolutionally conserved cysteine residue in the DNA binding domain of MEF2 transcription factors switches off their transcriptional activity. This nitrosylation event impairs both neurogenesis and neuronal survival in several neurodegenerative conditions, including Alzheimer’s disease and stroke.