| Literature DB >> 31348885 |
Moran Dvela-Levitt1, Maria Kost-Alimova2, Maheswarareddy Emani1, Eva Kohnert1, Rebecca Thompson1, Eriene-Heidi Sidhom1, Ana Rivadeneira1, Nareh Sahakian1, Julie Roignot1, Gregory Papagregoriou3, Monica S Montesinos1, Abbe R Clark1, David McKinney2, Juan Gutierrez2, Mark Roth2, Lucienne Ronco2, Esther Elonga2, Todd A Carter2, Andreas Gnirke2, Michelle Melanson2, Kate Hartland2, Nicolas Wieder1, Jane C-H Hsu2, Constantinos Deltas3, Rebecca Hughey4, Anthony J Bleyer5, Stanislav Kmoch5, Martina Živná6, Veronika Barešova6, Savithri Kota7, Johannes Schlondorff7, Myriam Heiman8, Seth L Alper7, Florence Wagner2, Astrid Weins9, Todd R Golub2, Eric S Lander10, Anna Greka11.
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.Entities:
Keywords: COP vesicles; ER stress; Golgi apparatus; cargo receptor; endoplasmic reticulum; epithelial cells; kidney; organoids; secretory pathway; unfolded protein response
Mesh：
Substances：
Year: 2019 PMID： 31348885 DOI： 10.1016/j.cell.2019.07.002
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582