| First Author | Dvela-Levitt M | Year | 2019 |
| Journal | Cell | Volume | 178 |
| Issue | 3 | Pages | 521-535.e23 |
| PubMed ID | 31348885 | Mgi Jnum | J:278341 |
| Mgi Id | MGI:6342696 | Doi | 10.1016/j.cell.2019.07.002 |
| Citation | Dvela-Levitt M, et al. (2019) Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy. Cell 178(3):521-535.e23 |
| abstractText | 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. |
