title: S-nitrosylation-mediated redox transcriptional switch modulates neurogenesis and neuronal cell death.
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.
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: sokamoto@sbmri.org.
authors.forename: Shu-Ichi
authors.initials: S
authors.lastname: Okamoto
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Bioinformatics and Systems Biology Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Cieplak
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Shing Fai
authors.initials: SF
authors.lastname: Chan
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Evgenia
authors.initials: E
authors.lastname: Kalashnikova
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Lujian
authors.initials: L
authors.lastname: Liao
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Sofiyan
authors.initials: S
authors.lastname: Saleem
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Han
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Arjay
authors.initials: A
authors.lastname: Clemente
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Nutter
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Sances
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Brechtel
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Haus
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Haun
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Sanz-Blasco
authors.affiliation: Bioinformatics and Systems Biology Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Xiayu
authors.initials: X
authors.lastname: Huang
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Zaremba
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Jiankun
authors.initials: J
authors.lastname: Cui
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Zezong
authors.initials: Z
authors.lastname: Gu
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Rana
authors.initials: R
authors.lastname: Nikzad
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Harrop
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: McKercher
authors.affiliation: Bioinformatics and Systems Biology Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Godzik
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: slipton@sbmri.org.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
mesh_terms: D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D064326:MEF2 Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis; D009569:Nitric Oxide / Q000378:metabolism*; D010084:Oxidation-Reduction; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D015533:Transcriptional Activation
chemical_list: D064326:MEF2 Transcription Factors; D009569:Nitric Oxide; D004247:DNA