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 GuRana Nikzad, Anne Harrop, Scott R. McKercher, Adam Godzik, John R. Yates, Stuart A. Lipton

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

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 invitro and invivo. Our data define a molecular switch whereby redox-mediated posttranslational modification controls both neurogenesis and neurodegeneration via a single transcriptional signaling cascade.

Original languageEnglish (US)
Pages (from-to)217-228
Number of pages12
JournalCell Reports
Volume8
Issue number1
DOIs
StatePublished - Jul 10 2014
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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