2019年7月25日出版的《细胞》杂志发表了来自麻省理工学院和哈佛大学的Anna Greka小组的研究成果。他们发现了小分子以TMED9为靶点，可以促进溶酶体降解，逆转蛋白病。

研究团队证明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。该课题组人员鉴定出一种小分子BRD4780，该分子可以清除患者细胞、基因敲入小鼠肾脏和患者肾脏器官内的MUC1-fs。MUC1-fs被困在含有运货受体TMED9的早期分泌途径囊泡内。BRD4780与TMED9结合，释放MUC1-fs，并将其重新转运，使其被溶酶体降解（TMED9缺失表型模拟效果）。他们的发现表明BRD4780有可能成为治疗MKD及其它毒性蛋白疾病的先导。总的来说，研究团队阐明了错误折叠蛋白质被运货受体捕获的新机制，以及将其释放和顺行运输到溶酶体的策略。

据介绍，细胞内错误折叠蛋白的积累可导致毒性蛋白病变，这类疾病无法做到靶向治疗。Mucin 1肾病(MKD)是由MUC1基因(MUC1-fs)的移码突变引起的。
 

附：英文原文

Title: Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy

Author: Moran Dvela-Levitt, Maria Kost-Alimova, Maheswarareddy Emani, Todd R. Golub, Eric S. Lander, Anna Greka

Issue&Volume: Volume 178 Issue 3

Abstract: 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 re-routes 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.

DOI: DOI:https://doi.org/10.1016/j.cell.2019.07.002

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)30741-X