NF-κB dictates the degradation pathway of IκBα
NF-κB dictates the degradation pathway of IκBα
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DOI：
10.1038/emboj.2008.73
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发表时间：
2008-05-07
期刊：
影响因子：
11.4
通讯作者：
Ghosh, Gourisankar
中科院分区：
文献类型：
--
作者：
Mathes, Erika;O'Dea, Ellen L.;Ghosh, Gourisankar
已知I κ B蛋白是NF-κ B活性的调节剂。它们与NF-κ B二聚体紧密结合，直到IKK引起的刺激响应性N-末端磷酸化触发它们的泛素化和蛋白酶体降解。已知I κ B α是一种不稳定的蛋白质，其快速降解在与NF-κ B结合后减慢，但不知道什么动力学机制控制总I κ B α的稳态水平。在这里，我们清楚地表明，两种降解途径控制I κ B α的水平。游离I κ B α降解不受IKK或泛素化的控制，但本质上受称为PEST结构域的C末端序列的控制。NF-κ B与I κ B α的结合掩盖了PEST结构域的蛋白酶体识别，排除了不依赖于泛素的降解;结合的I κ B α需要IKK磷酸化和泛素化以实现缓慢的基础降解。我们表明游离I κ B α蛋白快速降解的生物学要求;游离I κ B α降解的改变抑制NF-κ B活化。此外，我们发现游离和结合的I κ B α是IKK的相似底物，NF-κ B结合的I κ B α的优先磷酸化是由于NF-κ B B稳定I κ B α。
I kappa B proteins are known as the regulators of NF-kappa B activity. They bind tightly to NF-kappa B dimers, until stimulus-responsive N-terminal phosphorylation by IKK triggers their ubiquitination and proteasomal degradation. It is known that I kappa B alpha is an unstable protein whose rapid degradation is slowed upon binding to NF-kappa B, but it is not known what dynamic mechanisms control the steady-state level of total I kappa B alpha. Here, we show clearly that two degradation pathways control the level of I kappa B alpha. Free I kappa B alpha degradation is not controlled by IKK or ubiquitination but intrinsically, by the C-terminal sequence known as the PEST domain. NF-kappa B binding to I kappa B alpha masks the PEST domain from proteasomal recognition, precluding ubiquitin-independent degradation; bound I kappa B alpha then requires IKK phosphorylation and ubiquitination for slow basal degradation. We show the biological requirement for the fast degradation of the free I kappa B alpha protein; alteration of free I kappa B alpha degradation dampens NF-kappa B activation. In addition, we find that both free and bound I kappa B alpha are similar substrates for IKK, and the preferential phosphorylation of NF-kappa B-bound I kappa B alpha is due to stabilization of I kappa B alpha by NF-kappa B.