Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy
Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy
复制标题
DOI：
10.1016/j.cell.2019.07.002
复制
发表时间：
2019-07-25
期刊：
影响因子：
64.5
通讯作者：
Greka, Anna
中科院分区：
文献类型：
--
作者：
Dvela-Levitt, Moran;Kost-Alimova, Maria;Greka, Anna
细胞内错误折叠蛋白质的积累导致毒性蛋白质病变，没有靶向治疗的疾病。Mucin 1肾病（MKD）是由MUC1基因（MUC1-fs）的移码突变引起的。在这里，我们表明MKD是一种毒性蛋白病。细胞内MUC1-fs的积累激活了ATF6未折叠蛋白反应（UPR）分支。我们鉴定出BRD4780，这是一种清除患者细胞、敲入小鼠肾脏和患者肾脏类器官中的MUC1-fs的小分子。MUC1-fs被困在早期分泌途径的TMED9载货受体囊泡中。BRD4780结合TMED9，释放MUC1-fs，并将其引导至溶酶体降解，这一效应被TMED9缺失所复制。我们的研究结果表明BRD4780是治疗MKD和其他毒性蛋白病的有希望的先导。总的来说，我们阐明了货物受体捕获错误折叠蛋白的新机制，以及它们释放和顺行运输到溶酶体的策略。
Intracellular accumulation of misfolded proteins causes toxic proteinopathies, diseases without targeted therapies. Mucin 1 kidney disease (MKD) results from a frameshift mutation in the MUC1 gene (MUC1-fs). Here, we show that MKD is a toxic proteinopathy. Intracellular MUC1-fs accumulation activated the ATF6 unfolded protein response (UPR) branch. We identified BRD4780, a small molecule that clears MUC1-fs from patient cells, from kidneys of knockin mice and from patient kidney organoids. MUC1-fs is trapped in TMED9 cargo receptor-containing vesicles of the early secretory pathway. BRD4780 binds TMED9, releases MUC1-fs, and reroutes it for lysosomal degradation, an effect phenocopied by TMED9 deletion. Our findings reveal BRD4780 as a promising lead for the treatment of MKD and other toxic proteinopathies. Generally, we elucidate a novel mechanism for the entrapment of misfolded proteins by cargo receptors and a strategy for their release and anterograde trafficking to the lysosome.