Divergent Cysteines in FOXO3 and FOXO4 Mediate Paralog-Specific Redox Signaling

Reduction-oxidation (redox) signaling, the translation of an oxidative intracellular environment into a cellular response, is mediated by the reversible oxidation of specific cysteine thiols. The latter results in disulfide formation between protein (hetero)dimers that alter protein function until the cellular redox has returned to the basal state. We have previously shown that this mechanism promotes the nuclear localization and activity of the FOXO4 transcription factor. Here, we present evidence that FOXO3 and FOXO4 have acquired paralog-specific cysteines throughout vertebrate evolution. Using a proteome-wide screen we identified previously unknown redox-dependent FOXO3 interaction partners. The nuclear import receptor IPO7 forms a disulfide-dependent heterodimer with FOXO3, but not with FOXO4, which is required for reactive oxygen species (ROS)-induced nuclear translocation . These findings suggest that evolutionary acquisition of cysteines has contributed to functional divergence of FOXO paralogs.