Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy
Date
2019Author
Dvela-Levitt, MoranKost-Alimova, Maria
Emani, Maheswarareddy
Kohnert, Eva
Thompson, Rebecca
Sidhom, Eriene-Heidi
Rivadeneira, Ana
Sahakian, Nareh
Roignot, Julie
Papagregoriou, Gregory
Montesinos, Monica S.
Clark, Abbe R.
McKinney, David
Gutierrez, Juan
Roth, Mark
Ronco, Lucienne
Elonga, Esther
Carter, Todd A.
Gnirke, Andreas
Melanson, Michelle
Hartland, Kate
Wieder, Nicolas
Hsu, Jane C.-H.
![ORCID logo](https://orcid.org/sites/default/files/images/orcid_16x16.png)
Hughey, Rebecca
Bleyer, Anthony J.
Kmoch, Stanislav
Živná, Martina
Barešova, Veronika
Kota, Savithri
Schlondorff, Johannes
Heiman, Myriam
Alper, Seth L.
Wagner, Florence
Weins, Astrid
Golub, Todd R.
Lander, Eric S.
Greka, Anna
ISSN
1097-4172Source
CellVolume
178Issue
3Pages
521-5.35E+025Google Scholar check
Metadata
Show full item recordAbstract
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.