CCAAT enhancer binding protein and nuclear factor of activated T cells regulate HIV-1 LTR via a novel conserved downstream site in cells of the monocyte-macrophage lineage.
CCAAT enhancer binding protein and nuclear factor of activated T cells regulate HIV-1 LTR via a novel conserved downstream site in cells of the monocyte-macrophage lineage.
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激活T细胞的CCAAT增强子结合蛋白和核因子通过单核细胞巨噬细胞谱系细胞中的新型保守下游位点调节HIV-1 LTR。
DOI：
10.1371/journal.pone.0088116
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Wigdahl B
中科院分区：
文献类型：
--
作者：
Dahiya S;Liu Y;Nonnemacher MR;Dampier W;Wigdahl B
人类免疫缺陷病毒1型(HIV-1)启动子的转录调控是通过与起始点上游和下游存在的顺式作用元件相互作用而实现的。在电子转录因子结合分析中，HIV-1B亚型LTR序列揭示了潜在的下游CCAAT增强子结合蛋白(C/EBP)结合位点。这个结合位点(+158到+172)，命名为DS3，在3858个独特的B亚型LTR序列中发现67%是保守的，根据核苷酸序列和LTR中的物理位置进行分析。Ds3在其他亚型中也有很好的表现。有趣的是，DS3与先前发现的结合活化T细胞核因子(NFAT)家族成员的区域重叠。与C/eBP家族成员(C/eBPα和β)相比，NFATc2对ds3有更高的亲和力。在C/EBP结合方面，DS3能够有效地与低亲和力的上游C/EBP结合位点I竞争，这表明NFAT和C/EBP都被利用。此外，环孢菌素A治疗，已被证明可以防止NFAT亚型的去磷酸化和核转位，导致C/EBPα结合增强。在慢性感染的U1细胞中，在整合的HIV-1 LTR中，也验证了在ds3的相互作用。在基础和白介素6刺激的条件下，结合敲除的ds3只在单核巨噬细胞系的细胞中减少了HIV-1LTR的定向转录，而在T细胞起源的细胞中没有。因此，在单核-巨噬细胞系中，ds3的事件正向调节细胞中的HIV-1启动子。
Transcriptional control of the human immunodeficiency virus type 1 (HIV-1) promoter, the long terminal repeat (LTR), is achieved by interactions with cis-acting elements present both upstream and downstream of the start site. In silico transcription factor binding analysis of the HIV-1 subtype B LTR sequences revealed a potential downstream CCAAT enhancer binding protein (C/EBP) binding site. This binding site (+158 to+172), designated DS3, was found to be conserved in 67% of 3,858 unique subtype B LTR sequences analyzed in terms of nucleotide sequence as well as physical location in the LTR. DS3 was found to be well represented in other subtypes as well. Interestingly, DS3 overlaps with a previously identified region that bind members of the nuclear factor of activated T cells (NFAT) family of proteins. NFATc2 exhibited a higher relative affinity for DS3 as compared with members of the C/EBP family (C/EBP α and β). DS3 was able to compete efficiently with the low-affinity upstream C/EBP binding site I with respect to C/EBP binding, suggesting utilization of both NFAT and C/EBP. Moreover, cyclosporine A treatment, which has been shown to prevent dephosphorylation and nuclear translocation of NFAT isoforms, resulted in enhanced C/EBPα binding. The interactions at DS3 were also validated in an integrated HIV-1 LTR in chronically infected U1 cells. A binding knockout of DS3 demonstrated reduced HIV-1 LTR-directed transcription under both basal and interleukin-6-stimulated conditions only in cells of the monocyte-macrophage lineage cells and not in cells of T-cell origin. Thus, the events at DS3 positively regulate the HIV-1 promoter in cells of the monocyte-macrophage lineage.
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