INSERM, UMR_S 1014, Hôpital Paul Brousse, Villejuif 94800, France.
Sci Signal. 2013 Sep 3;6(291):ra79. doi: 10.1126/scisignal.2004496.
The innate and adaptive immune responses involve the stimulation of nuclear factor κB (NF-κB) transcription factors through the Lys(63) (K(63))-linked ubiquitylation of specific components of NF-κB signaling pathways. We found that ubiquitylated components of the NF-κB 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-κB and that it directly bound to K(63)-linked polyubiquitin chains. Knockdown of MTDH inhibited the accumulation of ubiquitylated NF-κB signaling components at the ER, reduced the extent of NF-κB 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-κB activation.
先天免疫和适应性免疫反应涉及通过核因子 κB (NF-κB) 信号通路特定成分的 Lys(63) (K(63))连接泛素化来刺激 NF-κB 转录因子。我们发现，细胞表面、促炎细胞因子受体或抗原受体结合后，NF-κB 途径的泛素化成分在内质网 (ER) 膜的胞质小叶上积累。通过质谱分析，我们发现 ER 锚定蛋白 MTDH (metadherin) 是这些 NF-κB 的泛素化激活剂的伴侣，并且它直接与 K(63)连接的多泛素链结合。MTDH 的敲低抑制了 ER 中泛素化 NF-κB 信号成分的积累，降低了 NF-κB 激活的程度，并减少了产生的促炎细胞因子的量。我们的观察结果突出了 ER 作为 NF-κB 激活的关键细胞内门户的一个意外方面。
