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Záznam pochází z PubMed

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
Montesinos, Monica S
Autor Montesinos, Monica S Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Clark, Abbe R
Autor Clark, Abbe R Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
McKinney, David
Autor McKinney, David Broad Institute of MIT and Harvard, Cambridge, MA, USA
Gutierrez, Juan
Autor Gutierrez, Juan Broad Institute of MIT and Harvard, Cambridge, MA, USA
Roth, Mark
Autor Roth, Mark Broad Institute of MIT and Harvard, Cambridge, MA, USA
Ronco, Lucienne
Autor Ronco, Lucienne Broad Institute of MIT and Harvard, Cambridge, MA, USA
Elonga, Esther
Autor Elonga, Esther Broad Institute of MIT and Harvard, Cambridge, MA, USA
Carter, Todd A
Autor Carter, Todd A Broad Institute of MIT and Harvard, Cambridge, MA, USA
Gnirke, Andreas
Autor Gnirke, Andreas Broad Institute of MIT and Harvard, Cambridge, MA, USA
Melanson, Michelle
Autor Melanson, Michelle Broad Institute of MIT and Harvard, Cambridge, MA, USA
Hartland, Kate
Autor Hartland, Kate Broad Institute of MIT and Harvard, Cambridge, MA, USA
Wieder, Nicolas
Autor Wieder, Nicolas Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Hsu, Jane C-H
Autor Hsu, Jane C-H Broad Institute of MIT and Harvard, Cambridge, MA, USA
Deltas, Constantinos
Autor Deltas, Constantinos Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus
Hughey, Rebecca
Autor Hughey, Rebecca Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Bleyer, Anthony J
Autor Bleyer, Anthony J Section on Nephrology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC, USA; Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
Kmoch, Stanislav
Autor Kmoch, Stanislav Section on Nephrology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC, USA; Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
Živná, Martina
Autor Živná, Martina Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
Barešova, Veronika
Autor Barešova, Veronika Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
Kota, Savithri
Autor Kota, Savithri Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
Schlondorff, Johannes
Autor Schlondorff, Johannes Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
Heiman, Myriam
Autor Heiman, Myriam Broad Institute of MIT and Harvard, Cambridge, MA, USA; The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, MIT, Cambridge, MA, USA
Alper, Seth L
Autor Alper, Seth L Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
Wagner, Florence
Autor Wagner, Florence Broad Institute of MIT and Harvard, Cambridge, MA, USA
Weins, Astrid
Autor Weins, Astrid Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
Golub, Todd R
Autor Golub, Todd R Broad Institute of MIT and Harvard, Cambridge, MA, USA
Lander, Eric S
Autor Lander, Eric S Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biology, MIT, Cambridge, MA, USA; Department of Systems Biology, Harvard Medical School, Boston, MA, USA
Greka, Anna
Autor Greka, Anna Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: agreka@broadinstitute.org

Cell. 2019 Jul 25 ; 178 (3) : 521-535.e23.

ISSN 1097-4172 | 0092-8674
Zdroj

Jazyk angličtina Země Spojené státy americké Médium print

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz https://www.medvik.cz/link/pmid31348885

Grantová podpora
R01 DK099465 NIDDK NIH HHS - United States

PubMed 31348885
DOI 10.1016/j.cell.2019.07.002
PII: S0092-8674(19)30741-X
Knihovny.cz E-zdroje

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.

Broad Institute of MIT and Harvard Cambridge MA USA

Broad Institute of MIT and Harvard Cambridge MA USA; Department of Biology MIT Cambridge MA USA; Department of Systems Biology Harvard Medical School Boston MA USA

Broad Institute of MIT and Harvard Cambridge MA USA; Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA USA

Broad Institute of MIT and Harvard Cambridge MA USA; The Picower Institute for Learning and Memory Department of Brain and Cognitive Sciences MIT Cambridge MA USA

Department of Medicine Beth Israel Deaconess Medical Center and Harvard Medical School Boston MA USA

Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA USA; Department of Pathology Brigham and Women's Hospital Boston MA USA

Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics Department of Biological Sciences University of Cyprus Nicosia Cyprus

Renal Electrolyte Division Department of Medicine University of Pittsburgh School of Medicine Pittsburgh PA USA

Research Unit for Rare Diseases Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University Prague Czech Republic

Section on Nephrology Wake Forest School of Medicine Medical Center Blvd Winston Salem NC USA; Research Unit for Rare Diseases Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University Prague Czech Republic

Komentář v

Nat Rev Nephrol. 2019 Oct;15(10):593. doi: 10.1038/s41581-019-0194-8. PubMed