Caspase-3-mediated cleavage of p65/RelA results in a carboxy-terminal fragment that inhibits IkappaBalpha and enhances HIV-1 replication in human T lymphocytes.
Caspase-3-mediated cleavage of p65/RelA results in a carboxy-terminal fragment that inhibits IkappaBalpha and enhances HIV-1 replication in human T lymphocytes.
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DOI：
10.1186/1742-4690-5-109
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发表时间：
2008-12-01
期刊：
影响因子：
3.3
通讯作者：
Alcamí J
中科院分区：
文献类型：
--
作者：
Coiras M;López-Huertas MR;Mateos E;Alcamí J
p65/RelA的降解参与了NF-κ B依赖性活性的抑制和凋亡的发生。然而，NF-κB降解的机制尚不清楚，并且可以根据细胞类型而变化。p65/RelA的切割可以产生一个氨基末端片段，该片段被证明是NF-κB的显性负性抑制剂，从而促进细胞凋亡。然而，相反的情况也已被描述，并且含有两个有效的反式激活结构域的羧基末端片段的产生也与细胞凋亡的发生有关。在这种情况下，p65/RelA的羧基末端片段（Δ NH 2 p65），在非凋亡的人T淋巴细胞活化后检测，已被研究。T细胞构成人类免疫缺陷病毒1型（HIV-1）的长寿细胞库之一。由于NF-κB是参与HIV-1转录起始的最重要的诱导元件，因此充分控制NF-κB应答对于T细胞存活和病毒传播都至关重要。其主要抑制剂IκBα构成NF-κB反应的主要终止子，其通过p65/RelA的降解来补充。在这项研究中，caspase-3介导的p65/RelA的羧基端片段，这是在活化的人外周血淋巴细胞（PBL）中检测到的功能进行了分析。产生这种截短的p65/RelA的细胞没有发生凋亡，但显示出高活力，尽管半胱天冬酶-3激活。Δ NH 2 p65缺失大部分DNA结合结构域，但保留了二聚化结构域、NLS和转录激活结构域。因此，它可以转位到细胞核，与NF-κB1/p50和IκBα结合，但不能结合-κB共有位点。然而，尽管Δ NH 2 p65本身缺乏转录活性，但它可以通过劫持IκBα以剂量依赖的方式增加NF-κB活性。因此，其表达导致野生型p65/RelA的持续反式激活活性，以及HIV-1在PBL中复制的改善。此外，PMA、PHA和TNFα激活的T细胞核中的Δ NH 2 p65均增加，证明这一现象与细胞活化有关。这些数据表明，存在一种新的机制，通过p65/RelA的羧基末端片段与IκBα结合，以保护野生型p65/RelA免受Iκ Bα抑制，从而维持人T细胞中NF-κB活性。
Degradation of p65/RelA has been involved in both the inhibition of NF-κB-dependent activity and the onset of apoptosis. However, the mechanisms of NF-κB degradation are unclear and can vary depending on the cell type. Cleavage of p65/RelA can produce an amino-terminal fragment that was shown to act as a dominant-negative inhibitor of NF-κB, thereby promoting apoptosis. However, the opposite situation has also been described and the production of a carboxy-terminal fragment that contains two potent transactivation domains has also been related to the onset of apoptosis. In this context, a carboxy-terminal fragment of p65/RelA (ΔNH2p65), detected in non-apoptotic human T lymphocytes upon activation, has been studied. T cells constitute one of the long-lived cellular reservoirs of the human immunodeficiency virus type 1 (HIV-1). Because NF-κB is the most important inducible element involved in initiation of HIV-1 transcription, an adequate control of NF-κB response is of paramount importance for both T cell survival and viral spread. Its major inhibitor IκBα constitutes a master terminator of NF-κB response that is complemented by degradation of p65/RelA. In this study, the function of a caspase-3-mediated carboxy-terminal fragment of p65/RelA, which was detected in activated human peripheral blood lymphocytes (PBLs), was analyzed. Cells producing this truncated p65/RelA did not undergo apoptosis but showed a high viability, in spite of caspase-3 activation. ΔNH2p65 lacked most of DNA-binding domain but retained the dimerization domain, NLS and transactivation domains. Consequently, it could translocate to the nucleus, associate with NF-κB1/p50 and IκBα, but could not bind -κB consensus sites. However, although ΔNH2p65 lacked transcriptional activity by itself, it could increase NF-κB activity in a dose-dependent manner by hijacking IκBα. Thus, its expression resulted in a persistent transactivation activity of wild-type p65/RelA, as well as an improvement of HIV-1 replication in PBLs. Moreover, ΔNH2p65 was increased in the nuclei of PMA-, PHA-, and TNFα-activated T cells, proving this phenomenon was related to cell activation. These data suggest the existence of a novel mechanism for maintaining NF-κB activity in human T cells through the binding of the carboxy-terminal fragment of p65/RelA to IκBα in order to protect wild-type p65/RelA from IκBα inhibition.
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DOI：
10.1046/j.1432-1327.2000.01421.x
发表时间：
2000-06-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Kaltschmidt, B;Kaltschmidt, C;Schmitz, ML
通讯作者：
Schmitz, ML
影响因子：
11.4
作者：
ALCAMI, J;DELERA, TL;ARENZANASEISDEDOS, F
通讯作者：
ARENZANASEISDEDOS, F
影响因子：
15.9
作者：
Baldwin, AS
通讯作者：
Baldwin, AS
影响因子：
5.4
作者：
ADACHI, A;GENDELMAN, HE;MARTIN, MA
通讯作者：
MARTIN, MA
影响因子：
8
作者：
de Lera, TL;Folgueira, L;Alcami, J
通讯作者：
Alcami, J