Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Cell. 2019 Jul 25;178(3):521-535.e23. doi: 10.1016/j.cell.2019.07.002.
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.
细胞内错误折叠蛋白质的积累会导致无靶向治疗方法的毒性蛋白病。粘蛋白 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。我们从嵌合小鼠的肾脏和患者的肾类器官中鉴定出了一种能清除患者细胞中 MUC1-fs 的小分子 BRD4780。MUC1-fs 被困在早期分泌途径中含有 TMED9 货物受体的囊泡中。BRD4780 与 TMED9 结合，释放 MUC1-fs，并将其重新定向到溶酶体进行降解，TMED9 缺失可模拟该作用。我们的发现揭示了 BRD4780 作为治疗 MKD 和其他毒性蛋白病的有前途的先导化合物。总的来说，我们阐明了货物受体捕获错误折叠蛋白质的新机制，以及释放和正向运输到溶酶体的策略。
