Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, China.
Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China.
Nucleic Acids Res. 2023 Mar 21;51(5):2195-2214. doi: 10.1093/nar/gkad057.
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.
NF-κB 激活了负责耐甲氧西林金黄色葡萄球菌 (MRSA) 诱导的肺部炎症和损伤的主要炎症反应途径。在这里，我们报告 Forkhead 盒转录因子 FOXN3 通过使 NF-κB 信号失活来改善 MRSA 诱导的肺部炎症性损伤。FOXN3 与 IκBα 竞争与异质核糖核蛋白-U (hnRNPU) 的结合，从而阻止 β-TrCP 介导的 IκBα 降解，导致 NF-κB 失活。FOXN3 被 p38 在 S83 和 S85 残基上直接磷酸化，这诱导其与 hnRNPU 解离，从而促进 NF-κB 激活。解离后，磷酸化的 FOXN3 变得不稳定并发生蛋白酶体降解。此外，hnRNPU 是 p38 介导的 FOXN3 磷酸化和随后磷酸化依赖性降解所必需的。功能上，FOXN3 磷酸化的基因缺失导致对 MRSA 诱导的肺部炎症性损伤具有很强的抵抗力。重要的是，FOXN3 磷酸化与肺部炎症性疾病呈临床正相关。这项研究揭示了一个以前未知的调节机制，该机制是 FOXN3 磷酸化在肺部感染炎症反应中不可或缺作用的基础。
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