p38-mediated FOXN3 phosphorylation modulates lung inflammation and injury through the NF-κB signaling pathway

• Published in: Nucleic acids research Vol. 51; no. 5; pp. 2195 - 2214
• Main Authors: Zhu, Xinxing, Huang, Beijia, Zhao, Fengting, Lian, Jie, He, Lixiang, Zhang, Yangxia, Ji, Longkai, Zhang, Jinghang, Yan, Xin, Zeng, Taoling, Ma, Chunya, Liang, Yinming, Zhang, Chen, Lin, Juntang
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 21.03.2023
• Subjects: Cell Cycle Proteins - metabolism; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene regulation, Chromatin and Epigenetics; Humans; I-kappa B Proteins; Methicillin-Resistant Staphylococcus aureus - metabolism; NF-kappa B - genetics; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha - metabolism; Phosphorylation; Pneumonia - genetics; Signal Transduction
• ISSN: 0305-1048; 1362-4962; 1362-4962
• DOI: 10.1093/nar/gkad057

Abstract NF-κB activates the primary inflammatory response pathway responsible for methicillin-resistant Staphylococcus aureus (MRSA)-induced lung inflammation and injury. Here, we report that the Forkhead box transcription factor FOXN3 ameliorates MRSA-induced pulmonary inflammatory injury by inactivating NF-κB signaling. FOXN3 competes with IκBα for binding to heterogeneous ribonucleoprotein-U (hnRNPU), thereby blocking β-TrCP-mediated IκBα degradation and leading to NF-κB inactivation. FOXN3 is directly phosphorylated by p38 at S83 and S85 residues, which induces its dissociation from hnRNPU, thus promoting NF-κB activation. After dissociation, the phosphorylated FOXN3 becomes unstable and undergoes proteasomal degradation. Additionally, hnRNPU is essential for p38-mediated FOXN3 phosphorylation and subsequent phosphorylation-dependent degradation. Functionally, genetic ablation of FOXN3 phosphorylation results in strong resistance to MRSA-induced pulmonary inflammatory injury. Importantly, FOXN3 phosphorylation is clinically positively correlated with pulmonary inflammatory disorders. This study uncovers a previously unknown regulatory mechanism underpinning the indispensable role of FOXN3 phosphorylation in the inflammatory response to pulmonary infection. Graphical Abstract Graphical Abstract In the unstimulated state, FOXN3 restrains NF-κB activation by impeding IκBα recruitment to hnRNPU. Under pro-inflammatory stimuli, p38 phosphorylates FOXN3 to induce its dissociation from hnRNPU for degradation, activating NF-κB signaling.