Nuclear IKKβ Is an Adaptor Protein for IκBα Ubiquitination and Degradation in UV-Induced NF-κB Activation
Nuclear IKKβ Is an Adaptor Protein for IκBα Ubiquitination and Degradation in UV-Induced NF-κB Activation
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DOI：
10.1016/j.molcel.2010.07.030
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发表时间：
2010-08-27
期刊：
影响因子：
16
通讯作者：
Kamata, Hideaki
中科院分区：
文献类型：
--
作者：
Tsuchiya, Yoshihiro;Asano, Tomoichiro;Kamata, Hideaki
促炎细胞因子使用I κ B激酶（IKK）复合物激活NF-κ B，所述I κ B激酶复合物在N末端位点磷酸化抑制性蛋白（I κ B），导致其在细胞质中的泛素化和降解。尽管紫外线（UV）照射不会导致IKK活性，但其通过I κ B α降解而无N-末端磷酸化，通过未知机制激活NF-κ B。在这里，我们描述了核IKK β在紫外线诱导的I κ B α降解的衔接功能。UV照射诱导I κ B α核转位并与IKK β结合，IKK β通过异质性核糖核蛋白-U（hnRNP-U）与β-TrCP组成性相互作用，导致I κ B α泛素化和降解。此外，酪蛋白激酶2（CK 2）和p38与IKK β相关，并通过C-末端位点的磷酸化促进I κ B α降解。因此，在UV诱导的NF-κ B活化中，核IKK β作为I κ B α降解的衔接蛋白。NF-κ B由核IKK β衔接蛋白激活，抑制抗凋亡基因表达，促进UV诱导的细胞死亡。
Proinflammatory cytokines activate NF-kappa B using the I kappa B kinase (IKK) complex that phosphorylates inhibitory proteins (I kappa Bs) at N-terminal sites resulting in their ubiquitination and degradation in the cytoplasm. Although ultraviolet (UV) irradiation does not lead to IKK activity, it activates NF-kappa B by an unknown mechanism through I kappa B alpha degradation without N-terminal phosphorylation. Here, we describe an adaptor function of nuclear IKK beta in UV-induced I kappa B alpha degradation. UV irradiation induces the nuclear translocation of I kappa B alpha and association with IKK beta, which constitutively interacts with beta-TrCP through heterogeneous ribonucleoprotein-U (hnRNP-U) leading to I kappa B alpha ubiquitination and degradation. Furthermore, casein kinase 2 (CK2) and p38 associate with IKK beta and promote I kappa B alpha degradation by phosphorylation at C-terminal sites. Thus, nuclear IKK beta acts as an adaptor protein for I kappa B alpha degradation in UV-induced NF-kappa B activation. NF-kappa B activated by the nuclear IKK beta adaptor protein suppresses anti-apoptotic gene expression and promotes UV-induced cell death.