S-nitrosylation-mediated redox transcriptional switch modulates neurogenesis and neuronal cell death

Cell Rep. 2014 Jul 10;8(1):217-28. doi: 10.1016/j.celrep.2014.06.005. Epub 2014 Jul 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • MEF2 Transcription Factors
  • Nitric Oxide
  • DNA

Associated data

  • GEO/GSE57184