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首页> 外文期刊>American Journal of Physiology >Ribosomal S6 kinase-1 modulates interleukin-1beta-induced persistent activation of NF-kappaB through phosphorylation of IkappaBbeta.
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Ribosomal S6 kinase-1 modulates interleukin-1beta-induced persistent activation of NF-kappaB through phosphorylation of IkappaBbeta.

机译：核糖体S6激酶1通过IkappaBbeta的磷酸化调节白介素1beta诱导的NF-kappaB的持续活化。

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摘要

Activation of NF-kappaB requires the phosphorylation and degradation of its associated inhibitory proteins, IkappaB. Previously, we reported that the extracellular signal-regulated kinase (ERK) is required for IL-1beta to induce persistent activation of NF-kappaB in cultured rat vascular smooth muscle cells (VSMCs). The present study examined the mechanism by which the ERK signaling cascade modulates the duration of NF-kappaB activation. In cultured rat VSMCs, IL-1beta activated ERK and induced degradation of both IkappaBalpha and IkappaBbeta, which was associated with nuclear translocation of both ribosomal S6 kinase (RSK)1 and NF-kappaB p65. RSK1, a downstream kinase of ERK, was associated with an IkappaBbeta/NF-kappaB complex, which was independent of the phosphorylation status of RSK1. Treatment of VSMCs with IL-1beta decreased IkappaBbeta in the RSK1/IkappaBbeta/NF-kappaB complex, an effect that was attenuated by inhibition of ERK activation. Knockdown of RSK1 by small interference RNA attenuated the IL-1beta-induced IkappaBbeta decrease without influencing ether ERK phosphorylation or the earlier IkappaBalpha degradation. By using recombinant wild-type and mutant IkappaBbeta proteins, both active ERK2 and RSK1 were found to directly phosphorylate IkappaBbeta, but only active RSK1 phosphorylated IkappaBbeta on Ser19 and Ser23, two sites known to mediate the subsequent ubiquitination and degradation. In conclusion, in the ERK signaling cascade, RSK1 is a key component that directly phosphorylates IkappaBbeta and contributes to the persistent activation of NF-kappaB by IL-1beta.
机译：NF-kappaB的激活需要其相关抑制蛋白IkappaB的磷酸化和降解。以前，我们报道了IL-1beta诱导培养的大鼠血管平滑肌细胞（VSMC）持续激活NF-κB所需的细胞外信号调节激酶（ERK）。本研究检查了ERK信号级联调节NF-κB激活持续时间的机制。在培养的大鼠VSMC中，IL-1beta激活ERK并诱导IkappaBalpha和IkappaBbeta降解，这与核糖体S6激酶（RSK）1和NF-kappaB p65的核易位有关。 ERK的下游激酶RSK1与IkappaBbeta / NF-kappaB复合物相关，该复合物与RSK1的磷酸化状态无关。用IL-1beta处理VSMC可降低RSK1 / IkappaBbeta / NF-kappaB复合体中的IkappaBbeta，这种作用因抑制ERK激活而减弱。通过小的干扰RNA抑制RSK1减弱了IL-1beta诱导的IkappaBbeta降低，而不会影响醚ERK磷酸化或更早的IkappaBalpha降解。通过使用重组野生型和突变型IkappaBbeta蛋白，发现活性ERK2和RSK1均可直接磷酸化IkappaBbeta，而只有活性RSK1磷酸化了Ser19和Ser23上的IkappaBbeta，这两个位点可介导随后的泛素化和降解。总之，在ERK信号级联反应中，RSK1是直接磷酸化IkappaBbeta并有助于IL-1beta持续激活NF-kappaB的关键成分。

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