Chen Lijian, Feng Lijie, Wang Xia, Du Jian, Chen Ying, Yang Wen, Zhou Chengyue, Cheng Li, Shen Yujun, Fang Shengyun, Li Jun, Shen Yuxian
1] School of Pharmacy, Anhui Medical University, Hefei 230032, Anhui, China [2] Institute of Biopharmaceuticals, Anhui Medical University, Hefei 230032, Anhui, China [3] Department of Anesthesiology of the First Affiliated Hospital, Anhui Medical University, Hefei 230022, Anhui, China.
1] School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui, China [2] Institute of Biopharmaceuticals, Anhui Medical University, Hefei 230032, Anhui, China.
Sci Rep. 2015 Feb 2;5:8133. doi: 10.1038/srep08133.
Inflammation can cause endoplasmic reticulum (ER) stress and therefore activates the unfolded protein response (UPR). ER stress and the consequent UPR have the potential to activate NF-κB. However, the factors mediating the crosstalk between ER stress and the NF-κB pathway remain unclear. Here, we determined that ER stress inducible protein Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) was up-regulated in autoimmune diseases and inflammatory disease models. Inflammation caused MANF to relocalize to the nuclei. MANF interacted with the DNA binding domain of p65 through its C-terminal SAP-like domain in the nuclei under the condition of inflammation or ER stress. MANF consequently inhibited p65-mediated transcriptional activation by interfering with the binding of p65 to its target genes promoters. Consistently, MANF suppressed the expressions of NF-κB-dependent target genes and the proliferation of inflammatory synoviocytes. These findings suggest that MANF may be a negative regulator of inflammation and mediate the crosstalk between the NF-κB pathway and ER stress.
炎症可导致内质网（ER）应激，进而激活未折叠蛋白反应（UPR）。ER应激及随之产生的UPR有可能激活核因子κB（NF-κB）。然而，介导ER应激与NF-κB信号通路之间相互作用的因素仍不清楚。在此，我们确定内质网应激诱导蛋白中脑星形胶质细胞源性神经营养因子（MANF）在自身免疫性疾病和炎症性疾病模型中上调。炎症导致MANF重新定位至细胞核。在炎症或内质网应激条件下，MANF在细胞核内通过其C端类SAP结构域与p65的DNA结合结构域相互作用。MANF进而通过干扰p65与其靶基因启动子的结合来抑制p65介导的转录激活。一致地，MANF抑制NF-κB依赖性靶基因的表达以及炎性滑膜细胞的增殖。这些发现表明，MANF可能是炎症的负调节因子，并介导NF-κB信号通路与内质网应激之间的相互作用。
