Cell Reports (Jul 2014)

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

  • 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 III,
  • Stuart A. Lipton

DOI
https://doi.org/10.1016/j.celrep.2014.06.005
Journal volume & issue
Vol. 8, no. 1
pp. 217 – 228

Abstract

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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.