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首页> 外文期刊>Molecular and Cellular Biology >Human T-Cell Leukemia Virus Type 1 Tax Induction of NF-κB Involves Activation of the IκB Kinase α (IKKα) and IKKβ Cellular Kinases
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Human T-Cell Leukemia Virus Type 1 Tax Induction of NF-κB Involves Activation of the IκB Kinase α (IKKα) and IKKβ Cellular Kinases

机译：人T细胞白血病病毒1型税诱导的NF-κB涉及IκB激酶α（IKKα）和IKKβ细胞激酶的激活。

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Tax corresponds to a 40-kDa transforming protein from the pathogenic retrovirus human T-cell leukemia virus type 1 (HTLV-1) that activates nuclear expression of the NF-κB/Rel family of transcription factors by an unknown mechanism. Tax expression promotes N-terminal phosphorylation and degradation of IκBα, a principal cytoplasmic inhibitor of NF-κB. Our studies now demonstrate that HTLV-1 Tax activates the recently identified cellular kinases IκB kinase α (IKKα) and IKKβ, which normally phosphorylate IκBα on both of its N-terminal regulatory serines in response to tumor necrosis factor alpha (TNF-α) and interleukin-1 (IL-1) stimulation. In contrast, a mutant of Tax termed M22, which does not induce NF-κB, fails to activate either IKKα or IKKβ. Furthermore, endogenous IKK enzymatic activity was significantly elevated in HTLV-1-infected and Tax-expressing T-cell lines. Transfection of kinase-deficient mutants of IKKα and IKKβ into either human Jurkat T or 293 cells also inhibits NF-κB-dependent reporter gene expression induced by Tax. Similarly, a kinase-deficient mutant of NIK (NF-κB-inducing kinase), which represents an upstream kinase in the TNF-α and IL-1 signaling pathways leading to IKKα and IKKβ activation, blocks Tax induction of NF-κB. However, plasma membrane-proximal elements in these proinflammatory cytokine pathways are apparently not involved since dominant negative mutants of the TRAF2 and TRAF6 adaptors, which effectively block signaling through the cytoplasmic tails of the TNF-α and IL-1 receptors, respectively, do not inhibit Tax induction of NF-κB. Together, these studies demonstrate that HTLV-1 Tax exploits a distal part of the proinflammatory cytokine signaling cascade leading to induction of NF-κB. The pathological alteration of this cytokine pathway leading to NF-κB activation by Tax may play a central role in HTLV-1-mediated transformation of human T cells, clinically manifested as the adult T-cell leukemia.
机译：Tax对应于一种来自致病性逆转录病毒人T细胞白血病病毒1型（HTLV-1）的40 kDa转化蛋白，该蛋白通过未知机制激活NF-κB/ Rel家族转录因子的核表达。税收表达促进了NF-κB的主要胞质抑制剂IκBα的N端磷酸化和降解。我们的研究现在表明，HTLV-1 Tax激活了最近鉴定的细胞激酶IκB激酶α（IKKα）和IKKβ，它们通常会在N端调节丝氨酸上磷酸化IκBα，以响应肿瘤坏死因子α（TNF-α）和白介素-1（IL-1）刺激。相反，称为M22的Tax突变体，其不诱导NF-κB，不能激活IKKα或IKKβ。此外，在感染HTLV-1和表达Tax的T细胞系中，内源性IKK酶活性显着提高。将激酶缺陷型IKKα和IKKβ突变体转染到人Jurkat T或293细胞中，也抑制了Tax诱导的NF-κB依赖的报告基因表达。同样，NIK的激酶缺失突变体（诱导NF-κB的激酶）代表导致IKKα和IKKβ活化的TNF-α和IL-1信号通路中的上游激酶，可阻止NF-κB的Tax诱导。但是，显然不涉及这些促炎性细胞因子途径中的质膜近端元件，因为TRAF2和TRAF6衔接子的显性负突变体分别有效地阻断了通过TNF-α和IL-1受体的细胞质尾巴发出的信号。抑制NF-κB的税收诱导。总之，这些研究表明HTLV-1 Tax利用促炎细胞因子信号传导级联的远端来导致NF-κB的诱导。该细胞因子途径导致通过Tax激活NF-κB的病理改变可能在HTLV-1介导的人类T细胞转化中发挥重要作用，临床表现为成人T细胞白血病。

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