Department of Cancer Biology, Division of Cellular and Molecular Biology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
Nat Commun. 2012;3:1061. doi: 10.1038/ncomms2068.
The persistent or excess activation of NF-κB causes various inflammatory and autoimmune diseases, but the molecular mechanisms that negatively regulate NF-κB activation are not fully understood. Here we show that p47, an essential factor for Golgi membrane fusion, associates with the NEMO subunit of the IκB kinase (IKK) complex upon TNF-α 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-α- 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.
NF-κB 的持续或过度激活会导致各种炎症和自身免疫性疾病，但负调控 NF-κB 激活的分子机制尚未完全阐明。在这里，我们发现 p47 是高尔基体膜融合的必需因子，在 TNF-α 或 IL-1 刺激下与 IκB 激酶 (IKK) 复合物的 NEMO 亚基结合，并抑制 IKK 激活。p47 结合到 Lys63 连接的和线性多泛素链上，这些泛素链在受到刺激时被连接到 NEMO 上。p47 与多泛素化的 NEMO 的结合触发了 NEMO 的溶酶体降解，从而抑制了 IKK 的激活。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。总之，我们的研究结果表明，p47 对于以与先前表征的负调节剂（如 A20 和 CYLD）不同的机制负调控刺激诱导的 IKK 激活至关重要。
