Dvela-Levitt M, Kost-Alimova M, Emani M, Kohnert E, Thompson R, Sidhom EH, Rivadeneira A, Sahakian N, Roignot J, Papagregoriou G, et al. Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy. Cell. 2019;178:521–535 e23.
NOTES
Dvela-Levitt, MoranKost-Alimova, MariaEmani, MaheswarareddyKohnert, EvaThompson, RebeccaSidhom, Eriene-HeidiRivadeneira, AnaSahakian, NarehRoignot, JuliePapagregoriou, GregoryMontesinos, Monica SClark, Abbe RMcKinney, DavidGutierrez, JuanRoth, MarkRonco, LucienneElonga, EstherCarter, Todd AGnirke, AndreasMelanson, MichelleHartland, KateWieder, NicolasHsu, Jane C-HDeltas, ConstantinosHughey, RebeccaBleyer, Anthony JKmoch, StanislavZivna, MartinaBaresova, VeronikaKota, SavithriSchlondorff, JohannesHeiman, MyriamAlper, Seth LWagner, FlorenceWeins, AstridGolub, Todd RLander, Eric SGreka, AnnaengResearch Support, Non-U.S. Gov'tCell. 2019 Jul 25;178(3):521-535.e23. doi: 10.1016/j.cell.2019.07.002.
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.
Last updated on 02/17/2021