Precision Medicine Technologies
Tools to Resolve Disease Complexity
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 reroutes
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