Sun S C, Harhaj E W, Xiao G, Good L
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
AIDS Res Hum Retroviruses. 2000 Nov 1;16(16):1591-6. doi: 10.1089/08892220050193001.
The Tax protein encoded by human T cell leukemia virus type 1 (HTLV-1) induces constitutive nuclear expression of the transcription factor NF-kappaB, causing aberrant expression of a large array of cellular genes. Tax activates NF-kappaB by stimulating the activity of the I-kappaB kinase (IKK), which in turn leads to phosphorylation and degradation of the NF-kappaB inhibitor I-kappaBalpha. In normal T cells, IKK activation occurs transiently on cellular stimulation through the T cell receptor (TCR) and the CD28 costimulatory molecule. However, this inducible kinase is constitutively activated in Tax-expressing and HTLV-1-infected T cells, which contributes to the deregulated nuclear expression of NF-kappaB. As a genetic approach to dissect the pathways mediating IKK activation by Tax and T cell activation signals, somatic cell mutagenesis was performed to isolate signaling-defective mutant Jurkat T cell lines. One of the mutant cell lines was shown to have a defect in NF-kappaB activation by both T cell mitogens and Tax. Interestingly, this mutant cell line lacks expression of the IKK regulatory protein, IKKgamma. Expression of exogenous IKKgamma in the mutant cells restored NF-kappaB activation, thus confirming the essential role of this regulatory factor in IKK activation by the cellular and viral stimuli. Mechanistic studies have shown that Tax physically interacts with IKKgamma via specific domains, including two homologous leucine zipper motifs present in IKKgamma. The Tax/IKKgamma interaction serves to recruit Tax to the IKK catalytic subunits, IKKalpha and IKKbeta, and this recruitment appears to be an essential mechanism by which Tax stimulates the activity of IKK.
人类嗜T细胞病毒1型（HTLV-1）编码的Tax蛋白可诱导转录因子NF-κB的组成型核表达，导致大量细胞基因的异常表达。Tax通过刺激I-κB激酶（IKK）的活性来激活NF-κB，进而导致NF-κB抑制剂I-κBα的磷酸化和降解。在正常T细胞中，IKK激活通过T细胞受体（TCR）和CD28共刺激分子在细胞受到刺激时短暂发生。然而，这种诱导性激酶在表达Tax和感染HTLV-1的T细胞中被组成型激活，这导致了NF-κB的核表达失调。作为一种剖析Tax介导的IKK激活途径和T细胞激活信号的遗传学方法，进行了体细胞诱变以分离信号缺陷型突变Jurkat T细胞系。其中一个突变细胞系显示出对T细胞有丝分裂原和Tax诱导的NF-κB激活存在缺陷。有趣的是，该突变细胞系缺乏IKK调节蛋白IKKγ的表达。在突变细胞中外源表达IKKγ可恢复NF-κB激活，从而证实了该调节因子在细胞和病毒刺激激活IKK中的重要作用。机制研究表明，Tax通过特定结构域与IKKγ发生物理相互作用，包括IKKγ中存在的两个同源亮氨酸拉链基序。Tax/IKKγ相互作用有助于将Tax招募到IKK催化亚基IKKα和IKKβ，这种招募似乎是Tax刺激IKK活性的关键机制。
