The Role of NF-κB Acetylation in Microglial Activation: Implications for Therapeutic Targeting in Neuroinflammation.

Abstract

Neuroinflammation is a hallmark of neurodegenerative diseases, largely driven by microglial activation. This study investigates the role of Nuclear Factor kappa B (NF-κB) acetylation, specifically at the lysine residues K122 and K314 in regulating microglial activity and its potential as a therapeutic target in neuroinflammatory conditions. Using wild-type and mutant NF-κB constructs, the impact of acetylation on nuclear translocation and transcriptional activity of NF-κB was analysed, with a focus on Suberoylanilide Hydroxamic Acid (SAHA), a histone deactylase inhibitor (HDACi). The findings indicate that acetylation at K314 is crucial for NF-κB’s nuclear retention and pro-inflammatory transcriptional activity, while K122 plays a lesser role. The K314Q mutant exhibited enhanced nuclear retention under inflammatory stimuli, whereas the K314R mutant was resistant to the effects of SAHA. These results highlight the importance of K314 acetylation in modulating NF-κB’s role in inflammation and suggest that HDACis like SAHA could be explored for targeted therapeutic interventions in neuroinflammation, particularly by modulating specific acetylation sites.