Protein kinase C-zeta mediates NF-kappa B activation in human immunodeficiency virus-infected monocytes
Protein kinase C-zeta mediates NF-kappa B activation in human immunodeficiency virus-infected monocytes
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DOI：
10.1128/jvi.70.1.223-231.1996
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发表时间：
1996-01-01
影响因子：
5.4
通讯作者：
Paya, CV
中科院分区：
文献类型：
--
作者：
Folgueira, L;McElhinny, JA;Paya, CV
调节人类免疫缺陷病毒（HIV）在主要细胞储库（如巨噬细胞）中持续存在的分子机制仍不清楚。NF-κ B是一种参与调节HIV长末端重复序列的转录因子，在HIV感染人巨噬细胞后被选择性激活。虽然很少的信息是什么信号转导途径介导的NF-κ B激活单核细胞-巨噬细胞，我们以前的工作表明，经典的蛋白激酶C（PKC）同工酶不参与HIV介导的NF-κ B激活。在这项研究中，我们集中在非典型PKC同工酶。PKC-ζ属于该家族，并且已知是其他细胞系统中NF-κ B活化的重要步骤。U937细胞的免疫印迹实验表明，PKC-zeta存在于这些细胞中，并且其表达可以被反义寡核苷酸（AO）下调。HIV介导的NF-κ B活化被AO选择性地还原为PKC-ζ。此外，PI的负显性分子（C-S（PKC-zeta（mut）与NF-κ B依赖性报告基因的共转染选择性抑制HIV，但不抑制佛波醇肉豆蔻酸酯乙酸酯或脂多糖介导的NF-κ B活化。从PKC-zeta（mut）不能干扰基础或佛波酯肉豆蔻酸酯诱导的CREB-或AP 1-依赖性转录活性得出结论，PKC-S在调节NF-κ B B中具有特异性。最后，我们证明了一个选择性抑制p24生产的HIV感染的人巨噬细胞时，处理AO PKC-ζ。总之，这些结果表明，非典型PKC同工酶，包括PKC-S，参与信号转导途径，通过该途径HIV感染导致NF-κ B在人单核细胞和巨噬细胞中的活化。
The molecular mechanisms regulating human immunodeficiency virus (HIV) persistence in a major cell reservoir such as the macrophage remain unknown. NF-kappa B is a transcription factor involved in the regulation of the HIV long terminal repeat and is selectively activated following HIV infection of human macrophages. Although little information as to what signal transduction pathways mediate NF-kappa B activation in monocytes-macrophages is available, our previous work indicated that classical protein kinase C (PKC) isoenzymes were not involved in the HIV-mediated NF-kappa B activation. In this study, we have focused on atypical PKC isoenzymes. PKC-zeta belongs to this family and is known to be an important step in NF-kappa B activation in other cell systems. Immunoblotting experiments with U937 cells demonstrate that PKC-zeta is present in these cells, and its expression can be downmodulated by antisense oligonucleotides (AO). The HIV-mediated NF-kappa B activation is selectively reduced by AO to PKC-zeta. In addition, cotransfection of a negative dominant molecule of PI(C-S (PKC-zeta(mut))) with NF-kappa B dependent reporter genes selectively inhibits the HIV but not phorbol myristate acetate- or lipopolysaccharide-mediated activation of NF-kappa B. That PKC-S is specific in regulating NF-kappa B is concluded from the inability of PKC-zeta(mut) to interfere with the basal or phorbol myristate acetate-inducible CREB- or AP1-dependent transcriptional activity. Lastly, we demonstrate a selective inhibition of p24 production by HIV-infected human macrophages when treated with AO to PKC-zeta. Altogether, these results suggest that atypical PKC isoenzymes, including PKC-S, participate in the signal transduction pathways by which HIV infection results in the activation of NF-kappa B in human monocytic cells and macrophages.