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; SANZ BLASCO S; 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

Cell Reports

Elsevier

Año: 2014 vol. 8 p. 1 - 12

2211-1247

Redox-mediated posttranslational modificationsrepresent a molecular switch that controls majormechanisms of cell function. Nitric oxide (NO) canmediate redox reactions via S-nitrosylation, representingtransfer of an NO group to a critical proteinthiol. NO is known to modulate neurogenesis andneuronal survival in various brain regions in disparateneurodegenerative conditions. However, a unifyingmolecular mechanism linking these phenomenaremains unknown. Here, we report that S-nitrosylationof myocyte enhancer factor 2 (MEF2) transcriptionfactors acts as a redox switch to inhibit both neurogenesisand neuronal survival. Structure-basedanalysis reveals that MEF2 dimerization creates apocket, facilitating S-nitrosylation at an evolutionallyconserved cysteine residue in the DNA bindingdomain. S-Nitrosylation disrupts MEF2-DNA bindingand transcriptional activity, leading to impaired neurogenesisand survival in vitro and in vivo. Our datadefine a molecular switch whereby redox-mediatedposttranslational modification controls both neurogenesisand neurodegeneration via a single transcriptionalsignaling cascade.