小分子向TMED9并促进溶酶体降解以逆转蛋白质病变
Moran Dvela-Levitt1, Maria Kost-Alimova2, Maheswarareddy Emani1
1Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Cell
|July 27, 2019
概括
一种新的小分子BRD4780通过向TMED9受体来清除有毒的Mucin 1病 (MKD) 蛋白聚合物. 这一发现为MKD和其他蛋白质病症提供了有前途的治疗策略.
科学领域:
- 肝脏病学
- 分子生物学
- 生物化学
背景情况:
- 有毒蛋白质病因于细胞内错误折叠的蛋白质积累,缺乏向治疗.
- 基因1病 (MKD) 是由MUC1基因框架转移突变 (MUC1- fs) 引起的,导致细胞内有毒积累.
- 通过MUC1-fs的积累激活了ATF6未折叠蛋白反应 (UPR) 途径.
研究的目的:
- 确定Mucin 1脏疾病 (MKD) 的治疗策略.
- 研究MUC1-fs细胞内积累和清除的机制.
- 探索货物受体在错误折叠蛋白质贩运中的作用.
主要方法:
- 查清除MUC1-fs的小分子.
- 使用来自患者的细胞,鼠标模型和器官.
- 研究BRD4780,MUC1-fs和TMED9载荷受体之间的相互作用.
主要成果:
- 在患者细胞,小鼠脏和器官中有效清除MUC1- fs.
- 在早期分泌途径中,MUC1-fs被隔离在含有TMED9的囊泡中.
- BRD4780与TMED9结合,释放MUC1-fs进行溶酶体降解,模仿TMED9的删除效应.
结论:
- BRD4780是Mucin 1脏病 (MKD) 的一个有前途的治疗.
- 这项研究揭示了一种错误折叠的蛋白质被载荷受体捕获的新机制.
- 针对TMED9提供了一种在有毒蛋白病症中释放和降解错误折叠的蛋白质的策略.
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