Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan.
J Biol Chem. 2010 Feb 12;285(7):4441-6. doi: 10.1074/jbc.M109.031476. Epub 2009 Dec 2.
We previously reported that human T cell lymphotropic virus 1 (HTLV-1) Tax oncoprotein constitutively activates transforming growth factor-beta-activated kinase 1 (TAK1). Here, we established Tax-positive HuT-102 cells stably transfected with a short hairpin RNA vector (HuT-shTAK1 cells) and investigated the physiological function of TAK1. Microarray analysis demonstrated that several interferon (IFN)-inducible genes, including chemokines such as CXCL10 and CCL5, were significantly down-regulated in HuT-shTAK1 cells. In contrast, Tax-mediated constitutive activation of nuclear factor-kappaB (NF-kappaB) was intact in HuT-shTAK1 cells. IFN-regulatory factor 3 (IRF3), a critical transcription factor in innate immunity to viral infection, was constitutively activated in a Tax-dependent manner. Activation of IRF3 and IRF3-dependent gene expressions was dependent on TAK1 and TANK-binding kinase 1 (TBK1). On the other hand, IRF4, another member in the IRF family of transcription factors overexpressed in a Tax-independent manner, negatively regulated TAK1-dependent IRF3 transcriptional activity. Together, HTLV-1 manipulates IFN signaling by regulating both positive and negative IRFs.
我们之前曾报道，人 T 细胞白血病病毒 1（HTLV-1）Tax 癌蛋白持续激活转化生长因子-β激活激酶 1（TAK1）。在这里，我们建立了 Tax 阳性 HuT-102 细胞的稳定转染短发夹 RNA 载体（HuT-shTAK1 细胞），并研究了 TAK1 的生理功能。微阵列分析表明，几种干扰素（IFN）诱导基因，包括趋化因子如 CXCL10 和 CCL5，在 HuT-shTAK1 细胞中显著下调。相比之下，Tax 介导的核因子-κB（NF-κB）的组成性激活在 HuT-shTAK1 细胞中是完整的。IRF3，一种在病毒感染先天免疫中至关重要的转录因子，以 Tax 依赖性方式持续激活。IRF3 的激活和 IRF3 依赖性基因表达依赖于 TAK1 和 TANK 结合激酶 1（TBK1）。另一方面，IRF4，另一种在 Tax 非依赖性方式下过度表达的 IRF 家族转录因子，负调节 TAK1 依赖性 IRF3 转录活性。总之，HTLV-1 通过调节正负 IRF 来操纵 IFN 信号。
