A SUMO-acetyl switch in PXR biology

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Nuclear receptors, including the pregnane X receptor (PXR), are regulated by post-translational modifications (PTMs).
• PXR (NR1I2) controls drug metabolism and transport in the liver and intestine, impacting disease states like cancer.
• PXR is known to undergo various PTMs, including phosphorylation, SUMOylation, and ubiquitination.

Purpose of the Study:

• To investigate the role of PXR acetylation in regulating its function.
• To elucidate the interplay between PXR acetylation and SUMOylation.
• To understand how these modifications affect PXR's transcriptional activity and localization.

Main Methods:

• Primary hepatocyte cultures and cell-based assays were utilized.
• PXR acetylation was assessed on lysine residues.
• SUMO-modification of PXR was analyzed in conjunction with acetylation.
• Pharmacologic inhibition of de-acetylation (trichostatin A) was employed.
• PXR's interaction with HDAC3/SMRT complex was examined.

Main Results:

• PXR is acetylated on lysine residues.
• Increased PXR acetylation promotes its SUMO-modification.
• Acetylation and SUMOylation of PXR are influenced by its association with the HDAC3/SMRT complex.
• Inhibition of de-acetylation alters PXR's cellular localization and transactivation capacity.

Conclusions:

• A SUMO-acetyl switch mechanism regulates PXR activity.
• Acetylation of PXR stimulates its SUMO-modification, promoting transcriptional repression.
• This PTM interplay is crucial for controlling PXR-target gene expression.