p47 negatively regulates IKK activation by inducing the lysosomal degradation of polyubiquitinated NEMO
p47 negatively regulates IKK activation by inducing the lysosomal degradation of polyubiquitinated NEMO
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DOI：
10.1038/ncomms2068
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发表时间：
2012-09-01
影响因子：
16.6
通讯作者：
Inoue, Jun-ichiro
中科院分区：
文献类型：
--
作者：
Shibata, Yuri;Oyama, Masaaki;Inoue, Jun-ichiro
NF-κ B的持续或过度活化导致各种炎症和自身免疫性疾病，但负调节NF-κ B活化的分子机制尚未完全了解。在这里，我们表明，p47，高尔基体膜融合的一个重要因素，与I κ B激酶（IKK）复合物的NEMO亚基TNF-α或IL-1刺激后，并抑制IKK激活。p47与Lys 63连接的线性多聚泛素链结合，在这种刺激下，所述多聚泛素链与NEMO缀合。p47与多泛素化NEMO的结合触发NEMO的溶酶体降解，从而抑制IKK活化。p47的沉默导致TNF-α或IL-1诱导的IKK激活增强，以及编码炎症介质的基因表达增加。两者合计，我们的研究结果表明，p47是至关重要的负调节刺激诱导的IKK激活的方式，是从以前的特点负调节，如A20和CYLD的机制不同。
The persistent or excess activation of NF-kappa B causes various inflammatory and autoimmune diseases, but the molecular mechanisms that negatively regulate NF-kappa B activation are not fully understood. Here we show that p47, an essential factor for Golgi membrane fusion, associates with the NEMO subunit of the I kappa B kinase (IKK) complex upon TNF-alpha or IL-1 stimulation, and inhibits IKK activation. p47 binds to Lys63-linked and linear polyubiquitin chains, which are conjugated to NEMO upon such stimulation. The binding of p47 to polyubiquitinated NEMO triggers the lysosomal degradation of NEMO, thereby inhibiting IKK activation. The silencing of p47 results in enhanced TNF-alpha- or IL-1-induced IKK activation, and an increased expression of genes encoding inflammatory mediators. Taken together, our results suggest that p47 is critical for negatively regulating stimulation-induced IKK activation in a manner that is mechanistically distinct from the previously characterized negative regulators, such as A20 and CYLD.