Phosphorylation of NF-κB p65 at Ser 468 controls its COMMD1-dependent ubiquitination and target gene-specific proteasomal elimination
Phosphorylation of NF-κB p65 at Ser 468 controls its COMMD1-dependent ubiquitination and target gene-specific proteasomal elimination
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DOI：
10.1038/embor.2009.10
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发表时间：
2009-04-01
期刊：
影响因子：
7.7
通讯作者：
Schmitz, Michael Lienhard
中科院分区：
文献类型：
--
作者：
Geng, Hui;Wittwer, Tobias;Schmitz, Michael Lienhard
核因子-κ B（NF-κ B）转录因子系统是控制几种重要生物学功能的关键组分，因此需要确保其活性正确终止的机制。在这里，我们确定了一个新的磷酸化/泛素化开关的NF-κ B网络，控制反式激活p65亚基的稳定性。肿瘤坏死因子诱导的p65在Ser 468处的磷酸化允许COMMD 1和cullin 2的结合，COMMD 1和cullin 2是介导p65泛素化的多聚体泛素连接酶复合物的组分。p65在Ser 468处的突变在很大程度上阻止了p65泛素化和蛋白酶体降解。可诱导的p65消除仅限于NF-κ B靶基因的一个子集，如Icam 1。因此，染色质免疫沉淀实验揭示了选择性招募Ser 468磷酸化的p65和COMMD 1的Icam 1启动子。p65在Ser 468的磷酸化导致泛素/蛋白酶体依赖性地去除染色质结合的p65，从而有助于选择性终止NF-κ B依赖性基因表达。
The nuclear factor-kappaB (NF-kappa B) transcription factor system is a crucial component that controls several important biological functions, thus raising the need for mechanisms that ensure the correct termination of its activity. Here, we identify a new phosphorylation/ubiquitination switch in the NF-kappa B network that controls the stability of the transactivating p65 subunit. Tumour necrosis factor-induced phosphorylation of p65 at Ser 468 allows binding of COMMD1 and cullin 2, components of a multimeric ubiquitin ligase complex mediating p65 ubiquitination. Mutation of p65 at Ser 468 largely prevents p65 ubiquitination and proteasomal degradation. Inducible p65 elimination is restricted to a subset of NF-kappa B target genes such as Icam1. Accordingly, chromatin immunoprecipitation experiments reveal the selective recruitment of Ser 468-phosphorylated p65 and COMMD1 to the Icam1 promoter. Phosphorylation of p65 at Ser 468 leads to ubiquitin/proteasome-dependent removal of chromatin-bound p65, thus contributing to the selective termination of NF-kappa B-dependent gene expression.