Helmholtz Centre Munich - German Research Centre for Environmental Health, Research Unit Gene Vectors, Marchioninistrasse 25, 81377, Munich, Germany.
German Centre for Infection Research (DZIF), Partner Site Munich, Munich, Germany.
Nat Commun. 2020 Feb 4;11(1):685. doi: 10.1038/s41467-020-14502-x.
IκB kinase 2 (IKK2) is well known for its pivotal role as a mediator of the canonical NF-κB pathway, which has important functions in inflammation and immunity, but also in cancer. Here we identify a novel and critical function of IKK2 and its co-factor NEMO in the activation of oncogenic c-Jun N-terminal kinase (JNK) signaling, induced by the latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV). Independent of its kinase activity, the TGFβ-activated kinase 1 (TAK1) mediates LMP1 signaling complex formation, NEMO ubiquitination and subsequent IKK2 activation. The tumor progression locus 2 (TPL2) kinase is induced by LMP1 via IKK2 and transmits JNK activation signals downstream of IKK2. The IKK2-TPL2-JNK axis is specific for LMP1 and differs from TNFα, Interleukin-1 and CD40 signaling. This pathway mediates essential LMP1 survival signals in EBV-transformed human B cells and post-transplant lymphoma, and thus qualifies as a target for treatment of EBV-induced cancer.
IKK 激酶 2（IKK2）作为经典 NF-κB 途径的中介因子而广为人知，该途径在炎症和免疫中具有重要功能，但也与癌症有关。在这里，我们发现了 IKK2 及其共同因子 NEMO 的一个新的关键功能，即在 EBV 的潜伏膜蛋白 1（LMP1）诱导的致癌性 c-Jun N 末端激酶（JNK）信号转导中的作用。独立于其激酶活性，转化生长因子β激活激酶 1（TAK1）介导 LMP1 信号复合物的形成、NEMO 的泛素化以及随后的 IKK2 激活。肿瘤进展基因座 2（TPL2）激酶通过 IKK2 被 LMP1 诱导，并在 IKK2 下游传递 JNK 激活信号。IKK2-TPL2-JNK 轴是 LMP1 特异性的，与 TNFα、白细胞介素 1 和 CD40 信号不同。该途径介导 EBV 转化的人 B 细胞和移植后淋巴瘤中必需的 LMP1 存活信号，因此可作为治疗 EBV 诱导癌症的靶点。
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