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首页> 外文期刊>Cellular Signalling >Suppression of NF-κB signaling by KEAP1 regulation of IKKβ activity through autophagic degradation and inhibition of phosphorylation
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Suppression of NF-κB signaling by KEAP1 regulation of IKKβ activity through autophagic degradation and inhibition of phosphorylation

机译：通过自噬降解和磷酸化抑制通过KEAP1调节IKKβ活性来抑制NF-κB信号传导

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摘要

IκB kinase β (IKKβ) plays a crucial role in biological processes, including immune response, stress response, and tumor development by mediating the activation of various signaling molecules such as NF-κB. Extensive studies on the mechanisms underlying IKK activation have led to the identification of new activators and have facilitated an understanding of the cellular responses related to NF-κB and other target molecules. However, the molecular processes that modulate IKK activity are still unknown. In this study, we show that KEAP1 is a new IKK binding partner, which is responsible for the down-regulation of TNFα-stimulated NF-κB activation. The E(T/S)GE motif, which is found only in the IKKβ subunit of the IKK complex, is essential for interaction with the C-terminal Kelch domain of KEAP1. Reduction of KEAP1 expression by small interfering RNA enhanced NF-κB activity, and up-regulated the expression of NF-κB target genes. Ectopic expression of KEAP1 decreased the expression of IKKβ, which was restored by an autophagy inhibitor. IKK phosphorylation stimulated by TNFα was blocked by KEAP1. Our data demonstrate that KEAP1 is involved in the negative regulation of NF-κB signaling through the inhibition of IKKβ phosphorylation and the mediation of autophagy-dependent IKKβ degradation.
机译：IκB激酶β（IKKβ）通过介导各种信号分子（如NF-κB）的激活，在生物过程（包括免疫应答，应激应答和肿瘤发展）中起着至关重要的作用。关于IKK激活机制的广泛研究已导致鉴定新的激活剂，并促进了对与NF-κB和其他靶分子有关的细胞应答的理解。但是，调节IKK活性的分子过程仍然是未知的。在这项研究中，我们表明KEAP1是一个新的IKK结合伴侣，它负责TNFα刺激的NF-κB激活的下调。仅在IKK复合体的IKKβ亚基中发现的E（T / S）GE基序对于与KEAP1的C末端Kelch域相互作用至关重要。通过小的干扰RNA减少KEAP1表达可增强NF-κB活性，并上调NF-κB靶基因的表达。 KEAP1的异位表达降低了IKKβ的表达，IKKβ的表达被自噬抑制剂恢复。 TNFα刺激的IKK磷酸化被KEAP1阻断。我们的数据表明，KEAP1通过抑制IKKβ磷酸化和介导自噬依赖性IKKβ降解而参与NF-κB信号的负调控。

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