Li Fei, Gao Beixue, Dong Hongxin, Shi Jingshan, Fang Deyu
Department of Pharmacology and the Key Laboratory of Basic Pharmacology of Guizhou Province, Zunyi Medical College, Zunyi, China; Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave, Chicago, IL, 60611, United States of America.
Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave, Chicago, IL, 60611, United States of America.
PLoS One. 2015 Mar 25;10(3):e0119955. doi: 10.1371/journal.pone.0119955. eCollection 2015.
By suppressing neuronal apoptosis, Icariin is a potential therapeutic drug for neuronal degenerative diseases. The molecular mechanisms of Icariin anti-apoptotic functions are still largely unclear. In this report, we found that Icariin induces the expression of Synoviolin, an endoplasmic reticulum (ER)-anchoring E3 ubiquitin ligase that functions as a suppressor of ER stress-induced apoptosis. The nuclear factor erythroid 2-related factor 1 (NFE2L1) is responsible for Icariin-mediated Synoviolin gene expression. Mutation of the NFE2L1-binding sites in a distal region of the Synoviolin promoter abolished Icariin-induced Synoviolin promoter activity, and knockdown of NFE2L1 expression prevented Icariin-stimulated Synoviolin expression. More importantly, Icariin protected ER stress-induced apoptosis of PC12 cells in a Synoviolin-dependent manner. Therefore, our study reveals Icariin-induced Synoviolin expression through NFE2L1 as a previously unappreciated molecular mechanism underlying the neuronal protective function of Icariin.
淫羊藿苷通过抑制神经元凋亡，是一种治疗神经退行性疾病的潜在药物。淫羊藿苷抗凋亡功能的分子机制仍不清楚。在本报告中，我们发现淫羊藿苷可诱导滑膜素的表达，滑膜素是一种内质网（ER）锚定的E3泛素连接酶，其作为ER应激诱导凋亡的抑制剂发挥作用。核因子红细胞2相关因子1（NFE2L1）负责淫羊藿苷介导的滑膜素基因表达。滑膜素启动子远端区域的NFE2L1结合位点突变消除了淫羊藿苷诱导的滑膜素启动子活性，敲低NFE2L1表达可阻止淫羊藿苷刺激的滑膜素表达。更重要的是，淫羊藿苷以滑膜素依赖的方式保护ER应激诱导的PC12细胞凋亡。因此，我们的研究揭示了淫羊藿苷通过NFE2L1诱导滑膜素表达，这是淫羊藿苷神经元保护功能背后一种以前未被认识的分子机制。
