The tax oncoprotein of human T-cell leukemia virus type 1 associates with and persistently activates IκB kinases containing IKKα and IKKβ
The tax oncoprotein of human T-cell leukemia virus type 1 associates with and persistently activates IκB kinases containing IKKα and IKKβ
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DOI：
10.1074/jbc.273.26.15891
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发表时间：
1998-06-26
影响因子：
4.8
通讯作者：
Ballard, DW
中科院分区：
文献类型：
--
作者：
Chu, ZL;DiDonato, JK;Ballard, DW
人T细胞白血病病毒1型（HTLV 1）的Tax癌蛋白通过涉及I kappa B α（一种NF-κ B相关胞质抑制剂）降解的机制长期激活转录因子NF-κ B B。税收诱导的I κ B α分解需要抑制剂Ser-32和Ser-36的磷酸化，这也是马槟榔处理的T淋巴细胞中NF-κ B瞬时活化的先决条件。然而，Tax如何与细胞NF-κ B/I κ B信号传导机制相互作用以产生慢性而不是短暂的NF-κ B应答仍不清楚。我们现在证明Tax与含有催化亚基IKK α和IKK β的酪氨酸诱导的I κ B激酶（IKK）复合物相关，IKK α和IKK β介导I κ B α在Ser-32和Ser-36的磷酸化。与它们在酪氨酸处理的细胞中的瞬时激活对应物不同，Tax相关形式的Wt在Tax转染子或HTLV 1感染的T淋巴细胞中具有组成性活性。此外，Tax的点突变消除了IKK结合功能，也阻止了Tax介导的IKK和NF-κ B B的活化。总之，这些发现表明，在HTLV 1感染的T细胞中NF-κ B的持续活化是由直接的Tax/IKK偶联机制介导的。
The Tax oncoprotein of human T-cell leukemia virus type 1 (HTLV1) chronically activates transcription factor NF-kappa B by a mechanism involving degradation of I kappa B alpha, an NF-kappa B-associated cytoplasmic inhibitor. Tax-induced breakdown of I kappa B alpha requires phosphorylation of the inhibitor at Ser-32 and Ser-36, which is also a prerequisite for the transient activation of NF-kappa B in cytokine-treated T lymphocytes. However, it remained unclear how Tax interfaces with the cellular NF-kappa B/I kappa B signaling machinery to generate a chronic rather than a transient NF-kappa B response. We now demonstrate that Tax associates with cytokine-inducible I kappa B kinase (IKK) complexes containing catalytic subunits IKK alpha and IKK beta, which mediate phosphorylation of I kappa B alpha at Ser-32 and Ser-36, Unlike their transiently activated counterparts in cytokine-treated cells, Tax-associated forms of Wt are constitutively active in either Tax transfectants or HTLV1-infected T lymphocytes. Moreover, point mutations in Tax that ablate its IKK-binding function also prevent Tax-mediated activation of IKK and NF-kappa B, Together, these findings suggest that the persistent activation of NF-kappa B in HTLV1-infected T-cells is mediated by a direct Tax/IKK coupling mechanism.