S-Nitrosylation-Mediated Redox Transcriptional Switch Modulates Neurogenesis and Neuronal Cell Death
Year: 2014
Type: article
Abstract: 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.
Source: Cell Reports
Authors: Shu-ichi Okamoto, Tomohiro Nakamura, Piotr Cieplak, Shing Fai Chan, Evgenia Kalashnikova, Lujian Liao, Sofiyan Saleem, Xuemei Han, Arjay Clemente, Anthony Nutter, Sam Sances, Christopher Brechtel, Daniel Haus, Florian Haun, Sara Sanz-Blasco, Xiayu Huang, Hao Li, Jeffrey D. Zaremba, Jiankun Cui, Zezong Gu, Rana Nikzad, Anne Harrop, Scott R. McKercher, Adam Godzik, John R. Yates, Stuart A. Lipton
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: National Institute of Mental Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Modeling Parkinson's Disease with Isogenic hiPSC-Derived Dopaminergic Neurons, La Jolla Interdisciplinary Neuroscience Center Cores, G336149179, Comprehensive Biology: Exploiting the Yeast Genome, Phosphoproteomic tools for synaptic vs. extrasynaptic NMDA receptor signaling, Cellular/Molecular Pathophysiology of Intellectual and Developmental Disabilities, La Jolla-Parkinson's Disease Center Grant, Cancer Center Support Grant (CCSG)
OpenAlex ID: W2140307910