Activation of NF-κB by the human T cell leukemia virus type I tax oncoprotein is associated with ubiquitin-dependent relocalization of IκB kinase
Activation of NF-κB by the human T cell leukemia virus type I tax oncoprotein is associated with ubiquitin-dependent relocalization of IκB kinase
复制标题
DOI：
10.1074/jbc.m611031200
复制
发表时间：
2007-02-09
影响因子：
4.8
通讯作者：
Harhaj, Edward W.
中科院分区：
文献类型：
--
作者：
Harhaj, Nicole S.;Sun, Shao-Cong;Harhaj, Edward W.
人类T细胞白血病病毒1型（HTLV-1）是成人T细胞白血病的病原体。HTLV-1编码一种反式激活蛋白Tax，它主要负责病毒的致癌特性。Tax通过解除各种细胞因子（包括转录因子NF-κ B）的活性调节来促进T细胞转化。Tax通过与调节亚基IKK γ的物理相互作用激活I κ B激酶（IKK），尽管目前还不清楚Tax是如何激活IKK复合物的。在这里，我们表明，税收调制IKK复合物的细胞定位。IKK在HTLV-1转化株和表达Tax的Jurkat细胞中从细胞质中的广泛分布重新定位到集中的核周“热点”。不能激活NF-κ B的Tax突变体没有观察到IKK的再定位，这表明只有激活形式的IKK被再定位。然而，IKK的重新定位严格依赖于Tax表达，因为它不发生在缺乏Tax表达的ATL细胞系中或用佛波醇12-肉豆蔻酸酯13-乙酸酯和离子霉素处理的Jurkat细胞中。此外，IKK γ是重新分布所必需的，因为缺乏IKK γ的细胞在Tax表达后不能重新定位IKK α。我们还发现Tax泛素化可能调节IKK的重新定位，因为Tax中三个关键赖氨酸残基的突变使其无法重新定位IKK并激活经典和非经典NF-κ B通路。最后，我们已经观察到，在Tax表达细胞的核周IKK与高尔基体共定位，并且用诺考达唑或布雷菲德菌素A破坏高尔基体导致IKK重新分布到细胞质。总之，这些结果表明，税收诱导IKK复合物的再定位在一个泛素依赖性的方式，和IKK复合物的亚细胞定位的动态变化可能是至关重要的税收功能。
Human T cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia. HTLV-1 encodes a trans-activating protein, Tax, which is largely responsible for the oncogenic properties of the virus. Tax promotes T cell transformation by deregulating the activity of various cellular factors, including the transcription factor NF-kappa B. Tax activates the I kappa B kinase (IKK) via physical interaction with the regulatory subunit, IKK gamma, although it is unknown precisely how Tax activates the IKK complex. Here we show that Tax modulates the cellular localization of the IKK complex. The IKKs relocalize from a broad distribution in the cytoplasm to concentrated perinuclear "hot spots" in both HTLV-1-transformed lines and in Tax-expressing Jurkat cells. Relocalization of IKK is not observed with Tax mutants unable to activate NF-kappa B, suggesting that only activated forms of IKK are relocalized. However, relocalization of IKK is strictly dependent on Tax expression because it does not occur in ATL cell lines that lack Tax expression or in Jurkat cells treated with phorbol 12-myristate 13-acetate and ionomycin. Furthermore, IKK gamma is required for redistribution because cells lacking IKK gamma were unable to relocalize IKK alpha upon expression of Tax. We also find that Tax ubiquitination likely regulates IKK relocalization because mutation of three critical lysine residues in Tax renders it unable to relocalize IKK and activate the canonical and noncanonical NF-kappa B pathways. Finally, we have observed that the perinuclear IKK in Tax-expressing cells colocalizes with the Golgi, and disruption of Golgi with either nocodazole or brefeldin A leads to a redistribution of IKK to the cytoplasm. Together, these results demonstrate that Tax induces relocalization of the IKK complex in a ubiquitin-dependent manner, and dynamic changes in the subcellular localization of the IKK complex may be critical for Tax function.