Reciprocal Regulation Between the SCF^FBXO24 Ubiquitin E3 Ligase and FoxP1 Protein

Area of Science:

• Molecular Biology
• Biochemistry
• Cell Biology

Background:

• Forkhead Box Protein P1 (FoxP1) is a critical transcriptional repressor involved in development and implicated in adult diseases like COPD, atherosclerosis, and heart failure.
• Dysregulation of FoxP1 protein levels contributes to disease pathogenesis, but the mechanism controlling its stability was unknown.
• While FoxP1 ubiquitination has been observed, the specific E3 ligase responsible for its degradation remained unidentified.

Purpose of the Study:

• To identify the E3 ubiquitin ligase responsible for regulating FoxP1 protein stability.
• To elucidate the regulatory mechanism and potential therapeutic implications of targeting this interaction.

Main Methods:

• Identification of FBXO24 as the E3 ligase for FoxP1 using biochemical assays.
• Co-localization and complex formation studies in lung epithelial cells.
• Analysis of FBXO24 knockout mice under cigarette smoke exposure.
• Investigation of the feedback loop between FoxP1 and FBXO24 transcription.

Main Results:

• FBXO24, an SCF complex subunit, was identified as the E3 ligase that ubiquitinates and regulates FoxP1 stability.
• FBXO24 depletion reversed unfolded protein response and cell death induced by FoxP1 loss.
• FBXO24 knockout mice showed increased FoxP1 levels and reduced unfolded protein response in lungs and heart after smoke exposure.
• A novel bidirectional regulation was discovered: FoxP1 suppresses FBXO24 transcription.

Conclusions:

• FBXO24 is the E3 ligase controlling FoxP1 ubiquitination and stability, impacting cellular responses in lung epithelium.
• This study reveals a unique substrate-E3 ligase feedback loop, expanding understanding of protein stability regulation.
• Targeting FBXO24 presents a potential therapeutic strategy for COPD, atherosclerosis, and heart failure by modulating FoxP1 levels.