SKP2 Regulates Pulmonary Inflammatory Injury Triggered by Bacterial Infection Through p27-Mediated Degradation of FOXN3.

Excessive inflammatory responses are a primary driver of acute lung injury, yet the underlying molecular mechanisms remain incompletely understood. In this study, we identify SKP2, an E3 ubiquitin ligase, as a critical negative regulator of pulmonary inflammation during methicillin-resistant Staphylococcus aureus (MRSA) infection. Mechanistically, SKP2 promotes the degradation of its direct substrate p27kip1 (p27), which functions as an activator of a noncanonical NF-κB signaling pathway. We further demonstrate that p27 facilitates the recruitment of p38 kinase to heterogeneous nuclear ribonucleoprotein-U (hnRNPU), leading to direct phosphorylation of the transcriptional repressor FOXN3 at serine residues 83 and 85. This dual phosphorylation event triggers subsequent proteasomal degradation of FOXN3, thereby relieving transcriptional repression and enabling NF-κB-driven activation of pro-inflammatory genes. In vivo, genetic ablation of Skp2 worsens pulmonary inflammatory injury, elevates neutrophil infiltration, and significantly reduces survival in MRSA-infected mice, and these effects are greatly rescued by concurrent p27 depletion. Collectively, our findings uncover the SKP2-p27-FOXN3 axis as a pivotal regulatory module in pulmonary inflammation and suggest that targeting this axis may offer a promising therapeutic strategy for bacterial infection-induced lung injury.