title: Redox-dependent control of FOXO/DAF-16 by transportin-1.
abstract: 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.
authors: Molecular Cancer Research, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
authors: Marrit
authors: M
authors: Putker
authors: Tobias
authors: T
authors: Madl
authors: Harmjan R
authors: HR
authors: Vos
authors: Hesther
authors: H
authors: de Ruiter
authors: Marieke
authors: M
authors: Visscher
authors: Maaike C W
authors: MC
authors: van den Berg
authors: Mohammed
authors: M
authors: Kaplan
authors: Hendrik C
authors: HC
authors: Korswagen
authors: Rolf
authors: R
authors: Boelens
authors: Michiel
authors: M
authors: Vermeulen
authors: Boudewijn M T
authors: BM
authors: Burgering
authors: Tobias B
authors: TB
authors: Dansen
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism; D003553:Cystine / Q000378:metabolism; D051858:Forkhead Transcription Factors; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010084:Oxidation-Reduction; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D028961:beta Karyopherins / Q000378:metabolism* / Q000502:physiology
chemical_list: D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; D017382:Reactive Oxygen Species; C108121:TNPO1 protein, human; D014157:Transcription Factors; D028961:beta Karyopherins; C108831:daf-16 protein, C elegans; D003553:Cystine