PDF(Pubmed)
Abstract：
Activation of the NF-κB pathway is strictly regulated to prevent excessive inflammatory and immune responses. In a well-known negative feedback model, IκBα-dependent NF-κB termination is a delayed response pattern in the later stage of activation, and the mechanisms mediating the rapid termination of active NF-κB remain unclear. Here, we showed IκBα-independent rapid termination of nuclear NF-κB mediated by CLK2, which negatively regulated active NF-κB by phosphorylating the RelA/p65 subunit of NF-κB at Ser180 in the nucleus to limit its transcriptional activation through degradation and nuclear export. Depletion of CLK2 increased the production of inflammatory cytokines, reduced viral replication and increased the survival of the mice. Mechanistically, CLK2 phosphorylated RelA/p65 at Ser180 in the nucleus, leading to ubiquitin‒proteasome-mediated degradation and cytoplasmic redistribution. Importantly, a CLK2 inhibitor promoted cytokine production, reduced viral replication, and accelerated murine psoriasis. This study revealed an IκBα-independent mechanism of early-stage termination of NF-κB in which phosphorylated Ser180 RelA/p65 turned off posttranslational modifications associated with transcriptional activation, ultimately resulting in the degradation and nuclear export of RelA/p65 to inhibit excessive inflammatory activation. Our findings showed that the phosphorylation of RelA/p65 at Ser180 in the nucleus inhibits early-stage NF-κB activation, thereby mediating the negative regulation of NF-κB.
摘要：
严格调节NF-κB途径的激活以防止过度的炎症和免疫应答。在众所周知的负反馈模型中，IκBα依赖性NF-κB终止是活化后期的延迟反应模式，介导活性NF-κB快速终止的机制尚不清楚。这里,我们显示了由CLK2介导的不依赖IκBα的核NF-κB的快速终止，其通过磷酸化核中Ser180处的NF-κB的RelA/p65亚基来负调节活性NF-κB，以限制其通过降解和核输出的转录激活。CLK2的消耗增加了炎性细胞因子的产生，减少病毒复制并增加小鼠的存活率。机械上,CLK2在细胞核中Ser180磷酸化RelA/p65，导致泛素-蛋白酶体介导的降解和胞质再分布。重要的是,CLK2抑制剂促进细胞因子的产生，减少病毒复制，加速鼠牛皮癣.这项研究揭示了NF-κB早期终止的IκBα非依赖性机制，其中磷酸化的Ser180RelA/p65关闭了与转录激活相关的翻译后修饰，最终导致RelA/p65的降解和核输出，以抑制过度的炎症激活。我们的发现表明，RelA/p65在细胞核中Ser180的磷酸化抑制早期NF-κB激活，从而介导NF-κB的负调节。
