Human immunodeficiency virus-1 Tat activates NF-κB via physical interaction with IκB-α and p65.
Human immunodeficiency virus-1 Tat activates NF-κB via physical interaction with IκB-α and p65.
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DOI：
10.1093/nar/gkr1224
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发表时间：
2012-04
影响因子：
14.9
通讯作者：
Quinto I
中科院分区：
文献类型：
--
作者：
Fiume G;Vecchio E;De Laurentiis A;Trimboli F;Palmieri C;Pisano A;Falcone C;Pontoriero M;Rossi A;Scialdone A;Fasanella Masci F;Scala G;Quinto I
核因子（NF）-κB是促炎基因的主要调节因子，在人类免疫缺陷病毒1（HIV-1）感染中上调。HIV-1引起NF-κB失调的机制与艾滋病免疫功能障碍有关。我们报道了在单轮HIV-1感染或单脉冲PMA刺激中，HIV-1达特反式激活因子通过劫持抑制剂IκB-α和阻止阻遏物与NF-κB复合物结合来激活NF-κB。此外，达特还与NF-κB的p65亚基结合，增加p65 DNA结合亲和力和转录活性。达特富含精氨酸和半胱氨酸的结构域分别是IκB-α和p65结合以及维持NF-κB活性所必需的。在一系列NF-κ B应答基因中，达特主要以p65依赖性方式激活MIP-1α表达，并与MIP-1α NF-κB增强子结合，从而促进p65募集并置换IκB-α; NF-κ B应答基因CSF 3、LTA、NFKBIA和TLR 2也获得了类似结果。我们的研究结果支持了一种新的NF-κB激活机制，即通过达特与IκB-α和p65的物理相互作用，并可能有助于进一步了解HIV-1对炎症反应的失调。
Nuclear factor (NF)-κB is a master regulator of pro-inflammatory genes and is upregulated in human immunodeficiency virus 1 (HIV-1) infection. Mechanisms underlying the NF-κB deregulation by HIV-1 are relevant for immune dysfunction in AIDS. We report that in single round HIV-1 infection, or single-pulse PMA stimulation, the HIV-1 Tat transactivator activated NF-κB by hijacking the inhibitor IκB-α and by preventing the repressor binding to the NF-κB complex. Moreover, Tat associated with the p65 subunit of NF-κB and increased the p65 DNA-binding affinity and transcriptional activity. The arginine- and cysteine-rich domains of Tat were required for IκB-α and p65 association, respectively, and for sustaining the NF-κB activity. Among an array of NF-κB-responsive genes, Tat mostly activated the MIP-1α expression in a p65-dependent manner, and bound to the MIP-1α NF-κB enhancer thus promoting the recruitment of p65 with displacement of IκB-α; similar findings were obtained for the NF-κB-responsive genes CSF3, LTA, NFKBIA and TLR2. Our results support a novel mechanism of NF-κB activation via physical interaction of Tat with IκB-α and p65, and may contribute to further insights into the deregulation of the inflammatory response by HIV-1.
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影响因子：
15.9
作者：
EMILIE, D;PEUCHMAUR, M;GALANAUD, P
通讯作者：
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影响因子：
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