NF-KB inducing kinase activates NF-KB transcriptional activity independently of IKB kinase γ through a p38 MAPK-dependent RelA phosphorylation pathway
NF-KB inducing kinase activates NF-KB transcriptional activity independently of IKB kinase γ through a p38 MAPK-dependent RelA phosphorylation pathway
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DOI：
10.1016/j.cellsig.2004.02.005
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发表时间：
2004-09-01
影响因子：
4.8
通讯作者：
Jobin, C
中科院分区：
文献类型：
--
作者：
Jijon, H;Allard, B;Jobin, C
分子和生化分析表明，核转录因子κ B（NF-κ B）诱导激酶（NIK）介导IKK激活和NF-κ B转录活性。然而，基因缺失研究表明，NIK触发基因表达，而不影响IkappaB α降解和NF-κ B DNA结合活性。为了研究NIK在NF-κ B转录活性中的作用，我们使用来自野生型（wt）和IkappaB激酶γ（IKK γ）基因缺陷（IKK-（γ-/-））小鼠的小鼠胚胎成纤维细胞（MEF）。我们报道，虽然TNF诱导的NF-κ B转录活性在IYK-γ（-/-）细胞中被消除，但腺病毒基因递送的NIK（Ad 5 NIK）仍然增强转录活性和IL-6 mRNA积累。此外，NIK通过刺激IKK-γ（-/-）细胞中RelA（S536）的反式激活结构域（S536）靶向NF-κ B的反式激活功能。有趣的是，在IKK-γ（-/-）细胞中，Ad 5 NIK而不是TNF诱导RelA S536和p38丝裂原活化蛋白激酶（MAPK）磷酸化。功能分析表明，Ad 5 NIK诱导的NF-κ B转录活性、IL-6 mRNA表达和RelA磷酸化被p38抑制剂S13203580抑制，表明该MAPK在NIK向NF-κ B的信号传导中起作用。这些数据首次证明存在IKK-γ非依赖性NIK/p38 MAPK依赖性信号通路，其通过RelA磷酸化激活NF-κ B并诱导促炎基因表达。(C)2004年爱思唯尔公司All rights reserved.
Molecular and biochemical analysis indicates that nuclear transcription factor kappaB (NF-kappaB)-inducing kinase (NIK) mediates IKK activation and NF-kappaB transcriptional activity. However, gene deletion studies suggest that NIK triggers gene expression without affecting IkappaBalpha degradation and NF-kappaB DNA binding activity. In order to investigate the role of NIK in NF-kappaB transcriptional activity, we used mouse embryonic fibroblasts (MEF) derived from wild-type (wt) and IkappaB kinase gamma (IKKgamma) gene deficient (IKK-(gamma-/-)) mice. We report that although TNF-induced NF-kappaB transcriptional activity is abolished in IYK-gamma(-/-) cells, adenoviral gene delivery of NIK (Ad5NIK) still enhanced transcriptional activity and IL-6 mRNA accumulation. Moreover, NIK targets the transactivation function of NF-kappaB through stimulation of the transactivation domain (TAD) of RelA (S536) in IKK-gamma(-/-) cells. Interestingly, Ad5NIK, but not TNF, induces RelA S536 and p38 mitogen-activated protein kinase (MAPK) phosphorylation in IKK-gamma(-/-) cells. Functional analysis demonstrated that Ad5NIK-induced NF-kappaB transcriptional activity, IL-6 mRNA expression and RelA phosphorylation are inhibited by the p38 inhibitor S13203580, suggesting a role for this MAPK in NIK signaling to NF-kappaB. These data demonstrate for the first time the presence of an IKK-gamma-independent NIK/p38 MAPK-dependent signaling pathway that activates NF-kappaB and induces pro-inflammatory gene expression through RelA phosphorylation. (C) 2004 Elsevier Inc. All rights reserved.