Journal
MOLECULAR CELL
Volume 49, Issue 4, Pages 730-742Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2012.12.014
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Funding
- NIH Office of Research Infrastructure Programs [P40 OD010440]
- Dutch Cancer Society (KWF Kankerbestrijding)
- ECHO
- Netherlands Organisation for Scientific Research (NWO)
- Austrian Academy of Sciences (APART) fellowship
- Bavarian Ministry of Sciences, Research and the Arts in the framework of the Bavarian Molecular Biosystems Research Network
- Netherlands Foundation for Scientific Research (NWO-CW)
- European Union (Bio-NMR project) [261863]
- Cancer Genomics Centre
- Centre for Biomedical Genetics
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Forkhead box O (FOXO; DAF-16 in worms) transcription factors, which are of vital importance in cell-cycle control, stress resistance, tumor suppression, and organismal lifespan, are largely regulated through nucleo-cytoplasmic shuttling. Insulin signaling keeps FOXO/DAF-16 cytoplasmic, and hence transcriptionally inactive. Conversely, as in loss of insulin signaling, reactive oxygen species (ROS) can activate FOXO/DAF-16 through nuclear accumulation. How ROS regulate the nuclear translocation of FOXO/DAF-16 is largely unknown. Cysteine oxidation can stabilize protein-protein interactions through the formation of disulfide-bridges when cells encounter ROS. Using a proteome-wide screen that identifies ROS-induced mixed disulfide-dependent complexes, we discovered several interaction partners of FOXo4, one of which is the nuclear import receptor transportin-1. We show that disulfide formation with transportin-1 is required for nuclear localization and the activation of FOXO4/DAF-16 induced by ROS, but not by the loss of insulin signaling. This molecular mechanism for nuclear shuttling is conserved in C. elegans and directly connects redox signaling to the longevity protein FOXO/DAF-16.
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