The Endoplasmic Reticulum Acts as a Platform for Ubiquitylated Components of Nuclear Factor κB Signaling
The Endoplasmic Reticulum Acts as a Platform for Ubiquitylated Components of Nuclear Factor κB Signaling
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DOI：
10.1126/scisignal.2004496
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发表时间：
2013-09-03
影响因子：
7.3
通讯作者：
Bidere, Nicolas
中科院分区：
文献类型：
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作者：
Alexia, Catherine;Poalas, Konstantinos;Bidere, Nicolas
先天和适应性免疫反应涉及通过NF-kappa B信号通路特定组分的Lys(63) （K-63）连锁泛素化刺激核因子κ B （NF-kappa B）转录因子。我们发现NF-kappa B通路的泛素化成分在细胞表面、促炎细胞因子受体或抗原受体参与后，在内质网（ER）膜的胞质小叶上积累。通过质谱分析，我们发现er锚定的蛋白metadinin （MTDH）是NF-kappa B泛素化激活因子的伙伴，它直接结合到k -63连接的多泛素链上。MTDH的下调抑制了内质网泛素化NF-kappa B信号成分的积累，降低了NF-kappa B的激活程度，减少了促炎细胞因子的产生。我们的观察突出了内质网作为nf - κ B激活的关键亚细胞通道的一个意想不到的方面。
The innate and adaptive immune responses involve the stimulation of nuclear factor kappa B (NF-kappa B) transcription factors through the Lys(63) (K-63)-linked ubiquitylation of specific components of NF-kappa B signaling pathways. We found that ubiquitylated components of the NF-kappa B pathway accumulated on the cytosolic leaflet of the endoplasmic reticulum (ER) membrane after the engagement of cell-surface, proinflammatory cytokine receptors or antigen receptors. Through mass spectrometric analysis, we found that the ER-anchored protein metadherin (MTDH) was a partner for these ubiquitylated activators of NF-kappa B and that it directly bound to K-63-linked polyubiquitin chains. Knockdown of MTDH inhibited the accumulation of ubiquitylated NF-kappa B signaling components at the ER, reduced the extent of NF-kappa B activation, and decreased the amount of proinflammatory cytokines produced. Our observations highlight an unexpected facet of the ER as a key subcellular gateway for NF-kappa B activation.