Zheng Caishang, Zheng Zhenhua, Zhang Zhenfeng, Meng Jin, Liu Yan, Ke Xianliang, Hu Qinxue, Wang Hanzhong
Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Science, Wuhan 430071, China.
Cell Signal. 2015 Dec;27(12):2343-54. doi: 10.1016/j.cellsig.2015.08.018. Epub 2015 Sep 1.
Precise regulation of NF-κB signaling pathways is essential to effective host immune response. However, the specific molecular mechanism underlying NF-κB activation by different stimuli is not fully understood. Here we demonstrate that IFIT5, one of the interferon induced tetratricopeptide repeat family members, enhances IKK phosphorylation and NF-κB activation through interacting with TAK1 and IKK. Following TNF-α treatment, IFIT5 interacted with TAK1 or IKK complex and synergized the recruitment of IKK to TAK1 in a dose dependent manner. Consistent with these observations, knockdown of IFIT5 decreased the recruitment of IKK to TAK1 and markedly weakened IKK phosphorylation, further reducing the production of NF-κB target genes IL-8 and ICAM-1. Moreover, we found that IFIT5 also promoted SeV-induced IKK phosphorylation and NF-κB activation by regulating the recruitment of IKK to TAK1. Our findings identify a previously unrecognized role of IFIT5 as a positive regulator in IKK phosphorylation and NF-κB activation, highlighting that IFIT5 serves as an important mediator in innate immunity.
精确调节核因子κB（NF-κB）信号通路对于有效的宿主免疫反应至关重要。然而，不同刺激激活NF-κB的具体分子机制尚未完全明确。在此，我们证明了干扰素诱导的四肽重复序列家族成员之一的IFIT5，通过与转化生长因子β激活激酶1（TAK1）和IκB激酶（IKK）相互作用，增强IKK磷酸化和NF-κB激活。在肿瘤坏死因子-α（TNF-α）处理后，IFIT5与TAK1或IKK复合物相互作用，并以剂量依赖的方式协同IKK募集到TAK1。与这些观察结果一致，敲低IFIT5可减少IKK募集到TAK1，并显著减弱IKK磷酸化，进一步降低NF-κB靶基因白细胞介素-8（IL-8）和细胞间黏附分子-1（ICAM-1）的产生。此外，我们发现IFIT5还通过调节IKK募集到TAK1来促进仙台病毒（SeV）诱导的IKK磷酸化和NF-κB激活。我们的研究结果确定了IFIT5作为IKK磷酸化和NF-κB激活的正向调节因子这一先前未被认识的作用，突出了IFIT5作为固有免疫中重要介质的作用。
