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Autor: Golub, Todd R

1 záznamů v Medvik Filtry

Článek

Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy

Dvela-Levitt, Moran
Autor Dvela-Levitt, Moran Broad Institute of MIT and Harvard, Cambridge, MA, USA Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Kost-Alimova, Maria
Autor Kost-Alimova, Maria Broad Institute of MIT and Harvard, Cambridge, MA, USA
Emani, Maheswarareddy
Autor Emani, Maheswarareddy Broad Institute of MIT and Harvard, Cambridge, MA, USA Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Kohnert, Eva
Autor Kohnert, Eva Broad Institute of MIT and Harvard, Cambridge, MA, USA Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Thompson, Rebecca
Autor Thompson, Rebecca Broad Institute of MIT and Harvard, Cambridge, MA, USA Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Sidhom, Eriene-Heidi
Autor Sidhom, Eriene-Heidi Broad Institute of MIT and Harvard, Cambridge, MA, USA Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Rivadeneira, Ana
Autor Rivadeneira, Ana Broad Institute of MIT and Harvard, Cambridge, MA, USA Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Sahakian, Nareh
Autor Sahakian, Nareh Broad Institute of MIT and Harvard, Cambridge, MA, USA Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Roignot, Julie
Autor Roignot, Julie Broad Institute of MIT and Harvard, Cambridge, MA, USA Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Papagregoriou, Gregory
Autor Papagregoriou, Gregory Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus

Cell. 2019 ; 178 (3) : 521-535.e23. [pub] 20190725

ISSN 1097-4172
Medvik
Zdroj

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.

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