Redox-dependent control of FOXO/DAF-16 by transportin-1

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Forkhead box O (FOXO) transcription factors regulate crucial cellular processes including stress resistance and lifespan.
• FOXO activity is primarily controlled by its nucleo-cytoplasmic shuttling, influenced by insulin signaling and reactive oxygen species (ROS).
• While insulin signaling sequesters FOXO in the cytoplasm, ROS promote its nuclear accumulation, but the precise mechanism remains unclear.

Purpose of the Study:

• To elucidate the molecular mechanism by which ROS induce the nuclear translocation of FOXO transcription factors.
• To identify novel interaction partners of FOXO4 involved in ROS-mediated signaling.
• To investigate the role of cysteine oxidation in regulating FOXO nuclear import.

Main Methods:

• Proteome-wide screening to identify ROS-induced mixed disulfide-dependent protein complexes.
• Biochemical assays to confirm interactions and functional consequences.
• Conservation studies in model organisms like C. elegans.

Main Results:

• Identified transportin-1 as a novel interaction partner of FOXO4, forming ROS-induced disulfide bridges.
• Demonstrated that disulfide formation between FOXO4 and transportin-1 is critical for ROS-induced nuclear localization.
• Showed this mechanism is specific to ROS-induced activation, not insulin signaling loss.
• Confirmed the conservation of this redox-dependent nuclear import mechanism in C. elegans.

Conclusions:

• Disulfide bond formation with transportin-1 is a key mechanism linking ROS signaling to FOXO nuclear import and activation.
• This finding provides a direct molecular link between cellular redox state and the regulation of the longevity protein FOXO.
• The conserved mechanism highlights the fundamental role of redox signaling in FOXO-mediated cellular functions.