Effect of Pseudomonas aeruginosa ExoU on airway epithelial cells through MUC1-C nuclear translocation

The opportunistic pathogen Pseudomonas aeruginosa plays a significant role in hospital-acquired pneumonia, with the secretion of ExoU - a virulence factor expressed by select P. aeruginosa strains - linked to poor clinical outcomes. This is due to ExoU's phospholipase A₂ activity, which triggers an uncontrolled inflammatory response, leading to severe pathologies. Here, we delve into ExoU's impact on mucin-1 (MUC1), a critical mucus component with immunomodulatory properties on pulmonary cell surfaces. Our findings reveal that infection of human respiratory epithelial cells by an ExoU-negative P. aeruginosa strain boosts MUC1 expression, yet ExoU secretion by the bacteria diminishes MUC1 mRNA and protein levels through JNK pathway disruption. Interestingly, despite reduced overall cell-associated MUC1 levels, ExoU prompts MUC1 accumulation within the nucleus, where the MUC1 cytoplasmic tail (MUC1-C) may act as a transcriptional coactivator. Notably, treating epithelial respiratory cell cultures with GO-201, a specific MUC1-C inhibitor, diminished CXCL-8 secretion induced by ExoU. In essence, our study highlights how infection by ExoU-producing P. aeruginosa strains suppresses MUC1 expression during infection, while enhancing MUC1-C translocation to the nucleus, where it plays a pro-inflammatory role. This unique mechanism sheds light on how ExoU can impact the host's defense against P. aeruginosa, potentially compromising host health.