OP36 - Redox control of FOXO through disulfide-dependent heterodimerization

Abstract

The forkheadbox O (FOXO) family of transcription factors regulates a variety of cellular programs, including cell cycle arrest, reactive oxygen species (ROS) scavenging, and apoptosis, and are of key importance in the decision over cell fate. In animal model systems it has been shown that FOXO is involved in the regulation of long lifespan. FOXO activity is tightly controlled by the insulin signaling pathway and by a multitude of ROS-induced posttranslational modifications. Over the past years my lab has discovered that cysteines in FOXO transcription factors become oxidized in response to redox signaling and that this leads to the formation of highly specific intermolecular disulfide formation with a number of regulators of FOXO activity. We have shown that ROS-induced Lysine acetylation on FOXO depends on the formation of an intermolecular disulfide with the p300 or CBP acetyltransferases. Furthermore, nuclear shuttling of FOXO is triggered by a shift in the cellular redox state towards more oxidizing conditions and this depends on intermolecular disulfide formation between FOXO and nuclear import receptors. By comparing cysteines present in human FOXO3 and FOXO4 isoforms by a quantitative proteomics approach we have identified paralog-specific redox signaling. We speculate that intermolecular disulfide formation could be a more common phenomenon in redox signaling and that it could serve to stabilize protein-protein interactions that otherwise would be of low affinity. By this means specific signaling cascades can be reversibly activated for as long as the cellular redox state remains more oxidizing.