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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Ubiquitin-dependent degradation of IkB alpha is mediated by a ubiquitin ligase Skpl/Cul 1/F-box protein FWD1I
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Ubiquitin-dependent degradation of IkB alpha is mediated by a ubiquitin ligase Skpl/Cul 1/F-box protein FWD1I

机译：IkB alpha的泛素依赖性降解是由泛素连接酶Skpl / Cul 1 / F-box蛋白FWD1I介导的

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摘要

Activation of the transcription factor nuclear factor kappa B (NF-kb) is controlled by proteolysis of its inhibitory subunit (lkB) via the ubiquitin-proteasome path- way. Signal-induced phosphorylation of IkBa by a large multisubunit complex containing IkB kinases is a prerequisite for ubiquitination. Here, we show that FWD1 (a mouse homologue of Slimb/beta TrCP), a member of the F-box/WD40- repeat proteins, is associated specifically with IkBa only when IkBa is phosphorylated. The introduction of FWD1 into cells Significantly promotes uniquitination and degradation of IkBa in concert with IkB kinases, resulting in nuclear trans- location of NF-kB. In addition, FWD1 strikingly evoked the ubiquitination of IxBa in the in vitro system. In contrast, a dominant-negative form of FWDI inhibits the uniquitination, leading to stabilization of IkBa. These results suggest that the substrate-specific degradation of IkBa is mediated by a skpl/Cull 1/F-box protein (SCF) FWD1 ubiquitin-ligase complex and that FWDl serves as an intracellular receptor for phosphorylated IkBa. Skpl/Cullin/F-box protein FWDI might play a critical role in transcriptional regulation of NF-kB through control of IkB protein stability.
机译：转录因子核因子κB（NF-kb）的激活通过泛素-蛋白酶体途径对其抑制性亚基（lkB）的蛋白水解来控制。包含IkB激酶的大型多亚基复合物的信号诱导的IkBa磷酸化是泛素化的先决条件。在这里，我们显示F-box / WD40-重复蛋白的成员FWD1（Slimb / beta TrCP的小鼠同源物）仅在IkBa磷酸化时才与IkBa关联。将FWD1引入细胞后，与IkB激酶协同作用可显着促进IkBa的单倍化和降解，从而导致NF-kB的核易位。此外，FWD1在体外系统中惊人地诱发了IxBa的泛素化。相比之下，FWDI的显性负型抑制单倍蛋白化，从而导致IkBa稳定。这些结果表明IkBa的底物特异性降解是由skpl / Cull 1 / F-box蛋白（SCF）FWD1泛素-连接酶复合物介导的，并且FWD1充当磷酸化IkBa的细胞内受体。 Skpl / Cullin / F-box蛋白FWDI可能通过控制IkB蛋白的稳定性在NF-kB的转录调控中发挥关键作用。

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