β-Arrestin inhibits NF-κB activity by means of its interaction with the NF-κB inhibitor IκBα
β-Arrestin inhibits NF-κB activity by means of its interaction with the NF-κB inhibitor IκBα
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DOI：
10.1073/pnas.0402851101
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发表时间：
2004-06
影响因子：
11.1
通讯作者：
D. Witherow;T. Garrison;W. Miller;R. Lefkowitz
中科院分区：
文献类型：
--
作者：
D. Witherow;T. Garrison;W. Miller;R. Lefkowitz
除了它们在七跨膜受体的脱敏和信号传导中的作用之外，β-抑制蛋白最近还涉及调节非七跨膜受体途径。通过酵母双杂交筛选，我们鉴定了NF-κB的抑制剂IκBα作为β-arrestin 1的结合伴侣。通过免疫沉淀实验评估β-arrestin 1和2与转染细胞中的IκBα相互作用。此外，已知调节IκBα功能的上游激酶，如IκB激酶α和β以及NF-κ B诱导激酶，也显示与β-arrestin相互作用。β-arrestin 1或β-arrestin 2的过表达导致NF-κB活性的显著抑制，如通过报告基因活性所测量的。NF-κB活性的抑制与用于NF-κB活化的刺激类型无关。相反，通过使用RNA干扰抑制β-arrestin 1而不是β-arrestin 2的表达，导致肿瘤坏死因子刺激的NF-κB活性增加3倍，这通过NF-κB迁移率变化分析来测量。这些数据揭示了β-arrestins在NF-κ B介导的基因调控中的作用。
In addition to their roles in desensitization and signaling of seven-membrane-spanning receptors, β-arrestins have been more recently implicated in regulating non-seven-membrane-spanning receptor pathways. By using a yeast two-hybrid screen, we identified the inhibitor of NF-κB, IκBα, as a binding partner of β-arrestin 1. Both β-arrestin 1 and 2 interact with IκBα in transfected cells as assessed by immunoprecipitation experiments. Additionally, upstream kinases known to regulate the function of IκBα, such as IκB kinase α and β and NF-κB-inducing kinase, were also shown to interact with β-arrestin. Overexpression of either β-arrestin 1 or β-arrestin 2 led to marked inhibition of NF-κB activity, as measured by reporter gene activity. Inhibition of NF-κB activity was independent of the type of stimulus used for NF-κB activation. Conversely, suppression of β-arrestin 1, but not β-arrestin 2, expression by using RNA interference led to a 3-fold increase in tumor necrosis factor-stimulated NF-κB activity as measured by NF-κB mobility-shift analysis. These data uncover a role of β-arrestins in the regulation of NF-κB-mediated gene regulation.