HIV-1 Tat inhibits IL-2 gene transcription through qualitative and quantitative alterations of the cooperative Rel/AP1 complex bound to the CD28RE/AP1 composite element of the IL-2 promoter
HIV-1 Tat inhibits IL-2 gene transcription through qualitative and quantitative alterations of the cooperative Rel/AP1 complex bound to the CD28RE/AP1 composite element of the IL-2 promoter
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DOI：
10.4049/jimmunol.166.7.4560
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发表时间：
2001-04-01
影响因子：
4.4
通讯作者：
Fresno, M
中科院分区：
文献类型：
--
作者：
González, E;Punzón, C;Fresno, M
细胞因子分泌失调在艾滋病发病机制中起着重要作用。在这里，我们证明 Jurkat 细胞中 HIV-1 Tat 蛋白的表达会导致 IL-2 基因转录的严重受损，但不会导致 TNF 基因转录的严重受损。有趣的是，这种抑制与病毒蛋白对 CD28RE/AP1 复合元件 (-164/-154) 反式激活的影响相关，但与在 IL-2 基因启动子的 NFAT/AP1 位点上观察到的影响无关，也与对 NF-κB 或 AP1 独立结合位点的影响无关。在 PMA 加钙离子载体刺激后，Tat 的内源表达诱导与 CD28RE/AP1 探针结合的特定蛋白复合物的量减少。这种效应伴随着 API 复合物的质量改变。因此，在野生型 Jurkat 细胞中，复合物中不存在 e-jun，而在表达 Tat 的细胞中，随着时间的推移，c-jun 逐渐被招募。相比之下，在野生型和 Jurkat Tat(+) 细胞中均检测到相似量的 c-rel 和少量 NFAT1。此外，Tat不仅诱导c-jun参与协同复合物，而且单独或与c-rel组合时其反式激活活性降低。因此，随着激活的进行，Tat 与该 rel/AP1 协同复合物成分的相互作用似乎会诱导该复合物发生定量和定性改变，从而导致 IL-2 基因转录减少。总而言之，我们的结果表明存在调整机制，使病毒蛋白能够特异性影响转录因子之间的合作相互作用。
Dysregulation of cytokine secretion plays an important role in AIDS pathogenesis. Here, we demonstrate that expression of HIV-1 Tat protein in Jurkat cells induces a severe impairment of IL-2 but not TNF gene transcription. Interestingly, this inhibition correlates with the effect of the viral protein on the transactivation of the CD28RE/AP1 composite element (-164/-154), but not with that observed on the NFAT/AP1 site of the IL-2 gene promoter, neither with the effect on NF-kappaB- nor AP1-independent binding sites. Endogenous expression of Tat induced a decrease in the amount of the specific protein complex bound to the CD28RE/AP1 probe after PMA plus calcium ionophore stimulation. This effect was accompanied by qualitative alterations of the API complex. Thus, in wild-type Jurkat cells, e-jun was absent from the complex, whereas in Tat-expressing cells, c-jun was increasingly recruited overtime. By contrast, similar amounts of c-rel and a small amount of NFAT1 were detected both in wild type and in Jurkat Tat(+) cells. Furthermore, Tat not only induced the participation of c-jun in the cooperative complex but also a decrease in its transactivation activity alone or in combination with c-rel. Thus, the interaction of Tat with the components of this rel/AP1 cooperative complex seems to induce quantitative and qualitative alterations of this complex as activation progresses, resulting in a decrease of IL-2 gene transcription. Altogether our results suggest the existence of tuned mechanisms that allow the viral protein to specifically affect cooperative interactions between transcription factors.