FOXK2 targeting by the SCF-E3 ligase subunit FBXO24 for ubiquitin mediated degradation modulates mitochondrial...

Area of Science:

• Molecular Biology
• Cellular Biology
• Pathogen-Host Interactions

Background:

• The transcription factor FOXK2 plays a vital role in numerous biological processes.
• Limited understanding exists regarding the protein turnover and regulation of FOXK2.

Purpose of the Study:

• To investigate the molecular mechanisms regulating FOXK2 protein stability.
• To explore the role of FOXK2 in cellular responses to bacterial pathogens and its impact on mitochondrial function.

Main Methods:

• Utilized cell culture models with virulent pathogens (Pseudomonas aeruginosa, Klebsiella pneumoniae).
• Investigated protein degradation pathways, including ubiquitin-proteasomal processing.
• Employed molecular techniques to identify protein interactions and functional domains (e.g., FBXO24 binding site).
• Assessed mitochondrial function through targeted gene depletion and mutant expression.
• Utilized a mouse model of experimental bacterial pneumonia.

Main Results:

• FOXK2 undergoes ubiquitin-proteasomal degradation in lung epithelia during infection with P. aeruginosa and K. pneumoniae.
• The E3 ligase subunit FBXO24 binds FOXK2's carboxyl terminus, mediating its polyubiquitylation and nuclear degradation.
• FOXK2 is present in mitochondria, and its depletion or mutation impairs mitochondrial function.
• In a bacterial pneumonia model, Fbxo24 heterozygous mice showed preserved mitochondrial function and FOXK2 levels compared to wild-type littermates.

Conclusions:

• Identified a novel mechanism of FOXK2 regulation via FBXO24-mediated degradation during bacterial infection.
• Demonstrated that FOXK2 abundance influences mitochondrial energetics.
• Suggests a new pathway for controlling mitochondrial function through the modulation of FOXK2 protein levels in response to pathogens.