C-terminal binding protein 2 interacts with JUNB to control macrophage inflammation

Area of Science:

• Molecular Biology
• Immunology
• Genetics

Background:

• Chronic inflammation is a major global health issue with limited treatment options.
• Understanding the mechanisms of inflammatory pathogenesis is crucial for developing effective therapies.
• Transcriptional co-repressors play a role in regulating gene expression, including inflammatory genes.

Purpose of the Study:

• To investigate the role of C-terminal binding proteins (CTBP) 1 and 2 in macrophage activation and inflammatory gene expression.
• To determine whether CTBP1 or CTBP2 is primarily responsible for controlling inflammatory responses.
• To explore the functional differences between oligomeric and monomeric forms of CTBP2 in regulating inflammation.

Main Methods:

• Utilized loss-of-function models in murine and human macrophages.
• Investigated the binding of CTBP2 to cis-regulatory elements of inflammatory genes.
• Performed rescue experiments with wild-type (WT) and mutant CTBP2.
• Conducted differential interactome profiling to compare WT and monomeric CTBP2 binding partners.

Main Results:

• CTBP2, but not CTBP1, was found to control inflammatory gene expression in macrophages.
• CTBP2 forms a co-repressor complex with transcription factors NF-κB and AP-1 at inflammatory gene loci.
• Oligomeric CTBP2 significantly attenuated inflammatory responses, whereas monomeric CTBP2 did not.
• Monomeric CTBP2 retained interactions with AP-1 and RNA polymerase II, promoting gene expression.

Conclusions:

• CTBP2 plays a critical role in fine-tuning inflammatory gene expression.
• The oligomeric state of CTBP2 is essential for its co-repressive function in inflammation.
• CTBP2 represents a potential therapeutic target for managing inflammatory diseases.