Association of Tat with promoters of PTEN and PP2A subunits is key to transcriptional activation of apoptotic pathways in HIV-infected CD4+ T cells.
Association of Tat with promoters of PTEN and PP2A subunits is key to transcriptional activation of apoptotic pathways in HIV-infected CD4+ T cells.
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DOI：
10.1371/journal.ppat.1001103
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发表时间：
2010-09-16
期刊：
影响因子：
6.7
通讯作者：
Aldovini A
中科院分区：
文献类型：
--
作者：
Kim N;Kukkonen S;Gupta S;Aldovini A
HIV-1感染的CD 4+原代T细胞中的凋亡是由PI 3 K和p53通路的改变触发的，它们聚集在FOXO 3a转录激活因子上。单独的达特可引起FOXO 3 a及其促凋亡靶基因的激活。为了了解达特如何影响这一途径，我们用达特进行了ChIP芯片实验。达特与PTEN和两个PP 2A亚基基因的启动子相关，但不与FOXO 3a启动子相关。PTEN和PP 2A编码磷酸酶，当达特表达时，磷酸酶的水平和活性增加。它们抵消Akt 1和FOXO 3a的磷酸化，从而激活FOXO 3a的转录活性。FOXO 3a促进Egr-1的转录增加，这可以进一步刺激PTEN的转录，从而加强导致FOXO 3a转录激活的途径。RNAi实验支持PTEN和PP 2A在Tat介导的级联反应的启动中的作用，这对细胞凋亡至关重要。在达特表达过程中，PTEN和PP 2A亚基mRNA的积累增加更可能是转录起始增加的结果，而不是RNAPII启动子近端暂停的缓解。Tat-PTEN和-PP 2A启动子相互作用提供了Tat介导的CD 4 + T细胞凋亡的机制解释。HIV感染导致CD 4 + T细胞（主要病毒细胞靶标）耗竭。这些细胞的破坏可由于细胞病变效应或凋亡而发生。HIV达特是一种蛋白质，可以促进感染和未感染细胞的凋亡过程，因为它在血浆中释放并进入未感染细胞。CD 4 + T细胞中的达特表达与FOXO 3 a的转录活性增加有关，FOXO 3 a是一种靶向促凋亡基因转录的因子。达特导致活化凋亡途径的机制是通过与磷酸酶PTEN和PP 2A的启动子结合并通过增加它们的水平。这些蛋白质的量增加导致pAKt 1的量减少和非磷酸化FOXO 3a的量增加，其从细胞质迁移到细胞核并增加其促凋亡靶基因的转录。这些结果，连同沉默PTEN和PP 2A并测量其活性的实验，鉴定了达特与PTEN和PP 2A启动子的关联作为Tat介导的细胞凋亡的起始事件。
Apoptosis in HIV-1-infected CD4+ primary T cells is triggered by the alteration of the PI3K and p53 pathways, which converge on the FOXO3a transcriptional activator. Tat alone can cause activation of FOXO3a and of its proapoptotic target genes. To understand how Tat affects this pathway, we carried out ChIP-Chip experiments with Tat. Tat associates with the promoters of PTEN and two PP2A subunit genes, but not with the FOXO3a promoter. PTEN and PP2A encode phosphatases, whose levels and activity are increased when Tat is expressed. They counteract phosphorylation of Akt1 and FOXO3a, and so activate transcriptional activity of FOXO3a. FOXO3a promotes increased transcription of Egr-1, which can further stimulate the transcription of PTEN, thereby reinforcing the pathway that leads to FOXO3a transcriptional activation. RNAi experiments support the role of PTEN and PP2A in the initiation of the Tat-mediated cascade, which is critical to apoptosis. The increased accumulation of PTEN and PP2A subunit mRNAs during Tat expression is more likely to be the result of increased transcription initiation and not relief of promoter-proximal pausing of RNAPII. The Tat-PTEN and -PP2A promoter interactions provide a mechanistic explanation of Tat-mediated apoptosis in CD4+ T cells. HIV infection leads to the depletion of CD4+ T cells, the major viral cell target. The destruction of these cells can occur because of cytopathic effect or apoptosis. HIV Tat is one of the proteins that can contribute to the apoptotic process of both infected and uninfected cells, as it is released in the plasma and enter uninfected cells. Tat expression in CD4+ T-cells is linked to increased transcriptional activity of FOXO3a, a factor that targets the transcription of pro-apoptotic genes. The mechanism by which Tat leads to activation apoptotic pathways is by associating with the promoters of the phospatases PTEN and PP2A and by increasing their levels. The increased amount of these proteins leads to a decreased amount of pAKt1 and increased amount of non-phosphorylated FOXO3a, which migrates from the cytoplasm to the nucleus and increases the transcription of its proapoptotic target genes. These results, together with experiments that silence PTEN and PP2A and measure their activities, identify the association of Tat with PTEN and PP2A promoters as the initiating event of Tat-mediated apoptosis.
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