Hubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China.
Hubei Key Laboratory of Cognitive and Affective Disorders, Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China; Department of Immunology, School of Medicine, Jianghan University, Wuhan, China.
Mol Immunol. 2024 Nov;175:1-9. doi: 10.1016/j.molimm.2024.09.001. Epub 2024 Sep 11.
The NSP14 protein of SARS-CoV-2 not only facilitates viral replication but also plays a pivotal role in activating the host immune system by enhancing cytokine production. In this study, we found that NSP14 markedly activated the activator protein 1 (AP-1) pathway by increasing the phosphorylation of ERK (p-ERK), which enters the nucleus and promotes AP-1 transcription. The screening of the main proteins of the ERK pathway revealed that NSP14 could interact with MEK, a kinase of ERK, and increase the level of phosphorylated MEK. The addition of the MEK inhibitor U0126 suppressed the level of p-ERK induced by NSP14 and partly blocked cytokine production, suggesting that NSP14 activates MEK to enhance AP-1 signaling. Further investigation demonstrated that the ExoN domain of NSP14 might be crucial for the interaction and activation of MEK. These results suggest a novel mechanism by which NSP14 of SARS-CoV-2 induces a proinflammatory response in the host.
新型冠状病毒的 NSP14 蛋白不仅有助于病毒复制，还通过增强细胞因子的产生在激活宿主免疫系统方面发挥关键作用。在这项研究中，我们发现 NSP14 通过增加 ERK（p-ERK）的磷酸化显著激活了激活蛋白 1（AP-1）途径，p-ERK 进入细胞核并促进 AP-1 转录。ERK 途径的主要蛋白筛选表明，NSP14 可以与 ERK 的激酶 MEK 相互作用并增加磷酸化 MEK 的水平。添加 MEK 抑制剂 U0126 抑制了 NSP14 诱导的 p-ERK 水平，并部分阻断了细胞因子的产生，这表明 NSP14 通过激活 MEK 来增强 AP-1 信号。进一步的研究表明，NSP14 的 ExoN 结构域可能对于 MEK 的相互作用和激活至关重要。这些结果提示了新型冠状病毒的 NSP14 诱导宿主炎症反应的一种新机制。
