You are here

Cell DOI:10.1016/j.cell.2019.07.002

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

Publication TypeJournal Article
Year of Publication2019
AuthorsDvela-Levitt, M, Kost-Alimova, M, Emani, M, Kohnert, E, Thompson, R, Sidhom, E-H, Rivadeneira, A, Sahakian, N, Roignot, J, Papagregoriou, G, Montesinos, MS, Clark, AR, McKinney, D, Gutierrez, J, Roth, M, Ronco, L, Elonga, E, Carter, TA, Gnirke, A, Melanson, M, Hartland, K, Wieder, N, Hsu, JC-H, Deltas, C, Hughey, R, Bleyer, AJ, Kmoch, S, Živná, M, Barešová, V, Kota, S, Schlondorff, J, Heiman, M, Alper, SL, Wagner, F, Weins, A, Golub, TR, Lander, ES, Greka, A
Date Published2019 Jul 25

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.


Alternate JournalCell
PubMed ID31348885
Additional Materials