Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Cell Rep. 2013 Mar 28;3(3):724-33. doi: 10.1016/j.celrep.2013.01.031. Epub 2013 Feb 28.
IκB kinase ε (IKKε, IKBKE) is a key regulator of innate immunity and a breast cancer oncogene, amplified in ~30% of breast cancers, that promotes malignant transformation through NF-κB activation. Here, we show that IKKε is modified and regulated by K63-linked polyubiquitination at lysine 30 and lysine 401. Tumor necrosis factor alpha and interleukin-1β stimulation induces IKKε K63-linked polyubiquitination over baseline levels in both macrophages and breast cancer cell lines, and this modification is essential for IKKε kinase activity, IKKε-mediated NF-κB activation, and IKKε-induced malignant transformation. Disruption of K63-linked ubiquitination of IKKε does not affect its overall structure but impairs the recruitment of canonical NF-κB proteins. A cIAP1/cIAP2/TRAF2 E3 ligase complex binds to and ubiquitinates IKKε. Altogether, these observations demonstrate that K63-linked polyubiquitination regulates IKKε activity in both inflammatory and oncogenic contexts and suggests an alternative approach to targeting this breast cancer oncogene.
IKKε（IκB kinase ε，IKBKE）是先天免疫的关键调节因子，也是乳腺癌的致癌基因，约 30%的乳腺癌中存在扩增，通过 NF-κB 激活促进恶性转化。在这里，我们表明 IKKε 可通过赖氨酸 30 和赖氨酸 401 上的 K63 连接多泛素化进行修饰和调节。肿瘤坏死因子-α和白细胞介素-1β刺激可在巨噬细胞和乳腺癌细胞系中诱导 IKKε 的 K63 连接多泛素化，超过基线水平，并且这种修饰对于 IKKε 激酶活性、IKKε 介导的 NF-κB 激活和 IKKε 诱导的恶性转化是必不可少的。破坏 IKKε 的 K63 连接泛素化不会影响其整体结构，但会损害规范 NF-κB 蛋白的募集。cIAP1/cIAP2/TRAF2 E3 连接酶复合物与 IKKε 结合并泛素化它。总而言之，这些观察结果表明 K63 连接多泛素化在炎症和致癌环境中调节 IKKε 的活性，并提示了针对这种乳腺癌致癌基因的另一种方法。
