Elucidation Of A Novel Mechanism For Faulty Protein Retention And A Therapeutic Strategy For Facilitated Lysosomal Removal

Intracellular accumulation of misfolded proteins causes toxic proteinopathies, diseases without targeted therapies. Mucin 1 kidney disease results from a frameshift mutation in the MUC1 gene (MUC1-fs). The main goal of this study is to investigate the cellular and molecular mechanism by which misfolded MUC1-fs accumulates and alters epithelial cell function, and to develop a mechanism-based therapy to reverse it. We found that the frameshift mutation results in toxic accumulation of the misfolded protein, through a previously unknown retention mechanism. The mutant protein was shown to accumulate in the early secretory pathway where it is trapped in TMED9 cargo receptor-enriched vesicles between the cis-Golgi and the ER. This accumulation induces ER stress, eventually leading to cell death. We have identified BRD4780, a small molecule that targets TMED9, releases MUC1-fs from early secretory compartments and reroutes it to the lysosome where it is degraded and removed from the cell. The compound cleared the mutant protein from patient cells, kidneys of knock-in mice and patient iPSC-derived kidney organoids. In summary, we have elucidated a novel molecular mechanism responsible for the retention of misfolded proteins, and discovered a promising small molecule as a therapeutic lead for toxic proteinopathies.