Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy.

Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy.

Cell (2019-07-28)

Moran Dvela-Levitt, Maria Kost-Alimova, Maheswarareddy Emani, Eva Kohnert, Rebecca Thompson, Eriene-Heidi Sidhom, Ana Rivadeneira, Nareh Sahakian, Julie Roignot, Gregory Papagregoriou, Monica S Montesinos, Abbe R Clark, David McKinney, Juan Gutierrez, Mark Roth, Lucienne Ronco, Esther Elonga, Todd A Carter, Andreas Gnirke, Michelle Melanson, Kate Hartland, Nicolas Wieder, Jane C-H Hsu, Constantinos Deltas, Rebecca Hughey, Anthony J Bleyer, Stanislav Kmoch, Martina Živná, Veronika Barešova, Savithri Kota, Johannes Schlondorff, Myriam Heiman, Seth L Alper, Florence Wagner, Astrid Weins, Todd R Golub, Eric S Lander, Anna Greka

PMID31348885

摘要

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.