SIRT1 mediates FOXA2 breakdown by deacetylation in a nutrient-dependent manner

Area of Science:

• Molecular Biology
• Metabolism
• Biochemistry

Background:

• The Forkhead transcription factor FOXA2 is crucial for liver metabolic homeostasis, particularly during fasting.
• The post-translational regulation of FOXA2 in response to nutrient availability is not fully elucidated.

Purpose of the Study:

• To investigate the role of acetylation in the post-translational control of FOXA2.
• To identify the specific lysine residues and the enzymes involved in FOXA2 acetylation and deacetylation.

Main Methods:

• Liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify acetylated residues.
• Co-immunoprecipitation assays to study protein interactions.
• Western blotting to assess protein stability and acetylation levels.
• Reporter assays to measure transcriptional activity.

Main Results:

• Five acetylated lysine residues in FOXA2 were identified.
• Sirtuin 1 (SIRT1) was found to interact with and deacetylate FOXA2, reducing its stability and transcriptional activity.
• Reduced interaction between FOXA2 and SIRT1 during nutrient withdrawal led to increased FOXA2 acetylation and stability in vivo.
• Multiple lysine residues beyond the initially identified five are involved in regulating FOXA2 acetylation and protein levels.

Conclusions:

• SIRT1-mediated deacetylation of FOXA2 plays a critical role in regulating liver metabolism.
• Nutrient availability dictates the interaction between SIRT1 and FOXA2, thereby controlling FOXA2 stability and function.
• Enhanced FOXA2 acetylation during starvation protects the protein from degradation, facilitating the execution of its transcriptional program to maintain metabolic homeostasis.