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.
- MeSH
- benzamidy chemie metabolismus farmakologie MeSH
- epitelové buňky cytologie metabolismus MeSH
- imidazolinové receptory antagonisté a inhibitory genetika metabolismus MeSH
- indukované pluripotentní kmenové buňky cytologie metabolismus MeSH
- ledviny cytologie metabolismus patologie MeSH
- lidé MeSH
- lyzozomy metabolismus MeSH
- malá interferující RNA metabolismus MeSH
- mucin 1 chemie genetika metabolismus MeSH
- myši transgenní MeSH
- myši MeSH
- nemoci ledvin metabolismus patologie MeSH
- posunová mutace MeSH
- RNA interference MeSH
- signální dráha UPR účinky léků MeSH
- transkripční faktor ATF6 metabolismus MeSH
- vezikulární transportní proteiny chemie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH