Hepatocyte growth factor suppresses proinflammatory NFκB activation through GSK3β inactivation in renal tubular epithelial cells
Hepatocyte growth factor suppresses proinflammatory NFκB activation through GSK3β inactivation in renal tubular epithelial cells
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DOI：
10.1074/jbc.m710396200
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发表时间：
2008-03-21
影响因子：
4.8
通讯作者：
Dworkin, Lance D.
中科院分区：
文献类型：
--
作者：
Gong, Rujun;Rifai, Abdalla;Dworkin, Lance D.
核因子kappaB的激活是所有炎症性疾病的中心的基本细胞事件。肝细胞生长因子(HGF)通过调节核因子-kappaB的活性，减轻多种器官系统的急性和慢性炎症；然而，确切的分子机制仍不清楚。在这里，我们报告了HGF通过GSK3β的失活抑制了NFkappa B p65的磷酸化，特异性地位于Ser-468位。RelA/p65的Ser-468位于GSK3β基序中，在体内和体外都能被GSK3β直接磷酸化，这意味着RelA/p65的Ser-468可能是GSK3β的底物。此外，RelA/p65的C末端含有GSK3β的共识对接序列的高度保守的结构域同源物。此外，该结构域是Ser-468有效磷酸化所必需的，对于relA/p65和GSK3β之间的物理相互作用也是不可或缺的。HGF通过使GSK3β失活，基本上阻断了这种相互作用。在功能上，RelA/p65的Ser-468的磷酸化是诱导依赖于促炎因子kappaB的特定亚集基因表达所必需的。HGF抑制Ser-468的磷酸化导致基因特异性抑制这些基因的表达。HGF在促炎因子kappaB激活中的作用一直被选择性的GSK3β抑制剂或通过RNA干扰敲除GSK3β所模拟，但在表达突变的不可抑制的GSK3β的细胞中基本上被取消。总之，我们的研究结果表明，HGF对NF-kappa B的激活有很强的抑制作用，这种作用是由GSK3β介导的，GSK3β是一个重要的信号转导因子，控制着RelA/p65的磷酸化特异性，并指导与炎症性肾脏疾病有关的选择性促炎细胞因子的转录。
Activation of NF kappa B is a fundamental cellular event central to all inflammatory diseases. Hepatocyte growth factor ( HGF) ameliorates both acute and chronic inflammation in a multitude of organ systems through modulating NF kappa B activity; nevertheless, the exact molecular mechanism remains uncertain. Here we report that HGF through inactivation of GSK3 beta suppresses NF kappa B p65 phosphorylation specifically at position Ser-468. The Ser-468 of RelA/p65 situates in a GSK3 beta consensus motif and could be directly phosphorylated by GSK3 beta both in vivo and in vitro, signifying Ser-468 of RelA/ p65 as a putative substrate for GSK3 beta. In addition, the C terminus of RelA/ p65 harbors a highly conserved domain homologue of the consensus docking sequence for GSK3 beta. Moreover, this domain was required for efficient phosphorylation of Ser- 468 and was indispensable for the physical interaction between RelA/ p65 and GSK3 beta. HGF substantially intercepted this interaction by inactivating GSK3 beta. Functionally, phosphorylation of Ser-468 of RelA/p65 was required for the induced expression of a particular subset of proinflammatory NF kappa B-dependent genes. Diminished phosphorylation at Ser- 468 by HGF resulted in a gene-specific inhibition of these genes' expression. The action of HGF on proinflammatory NF kappa B activation was consistently mimicked by a selective GSK3 beta inhibitor or GSK3 beta knockdown by RNA interference but largely abrogated in cells expressing the mutant uninhibitable GSK3 beta. Collectively, our findings suggest that HGF has a potent suppressive effect on NF kappa B activation, which is mediated by GSK3 beta, an important signaling transducer controlling RelA/ p65 phosphorylation specificity and directing the transcription of selective proinflammatory cytokines implicated in inflammatory kidney disease.