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Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy.
Dvela-Levitt, Moran; Kost-Alimova, Maria; Emani, Maheswarareddy; Kohnert, Eva; Thompson, Rebecca; Sidhom, Eriene-Heidi; Rivadeneira, Ana; Sahakian, Nareh; Roignot, Julie; Papagregoriou, Gregory; Montesinos, Monica S; Clark, Abbe R; McKinney, David; Gutierrez, Juan; Roth, Mark; Ronco, Lucienne; Elonga, Esther; Carter, Todd A; Gnirke, Andreas; Melanson, Michelle; Hartland, Kate; Wieder, Nicolas; Hsu, Jane C-H; Deltas, Constantinos; Hughey, Rebecca; Bleyer, Anthony J; Kmoch, Stanislav; Zivná, Martina; Baresova, Veronika; Kota, Savithri; Schlondorff, Johannes; Heiman, Myriam; Alper, Seth L; Wagner, Florence; Weins, Astrid; Golub, Todd R; Lander, Eric S; Greka, Anna.
Afiliação
  • Dvela-Levitt M; 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 M; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Emani M; 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 E; 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 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.
  • Sidhom EH; 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 A; 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 N; 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 J; 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 G; Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus.
  • Montesinos MS; 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 AR; 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 D; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Gutierrez J; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Roth M; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Ronco L; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Elonga E; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Carter TA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Gnirke A; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Melanson M; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Hartland K; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Wieder N; 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 JC; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Deltas C; Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus.
  • Hughey R; Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Bleyer AJ; 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 S; 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.
  • Zivná M; Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.
  • Baresova V; Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.
  • Kota S; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
  • Schlondorff J; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
  • Heiman M; 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 SL; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
  • Wagner F; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Weins A; 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 TR; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Lander ES; 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 A; 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 ; 178(3): 521-535.e23, 2019 07 25.
Article em En | MEDLINE | ID: mdl-31348885
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Benzamidas / Compostos Bicíclicos com Pontes / Proteínas de Transporte Vesicular / Heptanos / Lisossomos Tipo de estudo: Prognostic_studies Idioma: En Revista: Cell Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Benzamidas / Compostos Bicíclicos com Pontes / Proteínas de Transporte Vesicular / Heptanos / Lisossomos Tipo de estudo: Prognostic_studies Idioma: En Revista: Cell Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos