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Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy

Dvela-Levitt, Moran
Author 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
Author Kost-Alimova, Maria Broad Institute of MIT and Harvard, Cambridge, MA, USA
Emani, Maheswarareddy
Author 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
Author 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
Author 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
Author 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
Author 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
Author 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
Author 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
Author 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
Author 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
Author 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
Author McKinney, David Broad Institute of MIT and Harvard, Cambridge, MA, USA
Gutierrez, Juan
Author Gutierrez, Juan Broad Institute of MIT and Harvard, Cambridge, MA, USA
Roth, Mark
Author Roth, Mark Broad Institute of MIT and Harvard, Cambridge, MA, USA
Ronco, Lucienne
Author Ronco, Lucienne Broad Institute of MIT and Harvard, Cambridge, MA, USA
Elonga, Esther
Author Elonga, Esther Broad Institute of MIT and Harvard, Cambridge, MA, USA
Carter, Todd A
Author Carter, Todd A Broad Institute of MIT and Harvard, Cambridge, MA, USA
Gnirke, Andreas
Author Gnirke, Andreas Broad Institute of MIT and Harvard, Cambridge, MA, USA
Melanson, Michelle
Author Melanson, Michelle Broad Institute of MIT and Harvard, Cambridge, MA, USA
Hartland, Kate
Author Hartland, Kate Broad Institute of MIT and Harvard, Cambridge, MA, USA
Wieder, Nicolas
Author 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
Author Hsu, Jane C-H Broad Institute of MIT and Harvard, Cambridge, MA, USA
Deltas, Constantinos
Author Deltas, Constantinos Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus
Hughey, Rebecca
Author Hughey, Rebecca Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Bleyer, Anthony J
Author 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
Author 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
Author Živná, Martina Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
Barešova, Veronika
Author Barešova, Veronika Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
Kota, Savithri
Author Kota, Savithri Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
Schlondorff, Johannes
Author Schlondorff, Johannes Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
Heiman, Myriam
Author 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
Author Alper, Seth L Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
Wagner, Florence
Author Wagner, Florence Broad Institute of MIT and Harvard, Cambridge, MA, USA
Weins, Astrid
Author 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
Author Golub, Todd R Broad Institute of MIT and Harvard, Cambridge, MA, USA
Lander, Eric S
Author 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
Author 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
Source

Language English Country United States Media print

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link https://www.medvik.cz/link/pmid31348885

Grant support
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-resources

Keywords
COP vesicles, ER stress, Golgi apparatus, cargo receptor, endoplasmic reticulum, epithelial cells, kidney, organoids, secretory pathway, unfolded protein response,
MeSH
Benzamides chemistry metabolism pharmacology MeSH
Epithelial Cells cytology metabolism MeSH
Heptanes pharmacology therapeutic use MeSH
Imidazoline Receptors antagonists & inhibitors genetics metabolism MeSH
Induced Pluripotent Stem Cells cytology metabolism MeSH
Kidney cytology metabolism pathology MeSH
Humans MeSH
Lysosomes drug effects metabolism MeSH
RNA, Small Interfering metabolism MeSH
Mucin-1 chemistry genetics metabolism MeSH
Bridged Bicyclo Compounds pharmacology therapeutic use MeSH
Mice, Transgenic MeSH
Mice MeSH
Kidney Diseases metabolism pathology MeSH
Frameshift Mutation MeSH
RNA Interference MeSH
Unfolded Protein Response drug effects MeSH
Activating Transcription Factor 6 metabolism MeSH
Vesicular Transport Proteins chemistry metabolism MeSH
Animals MeSH
Check Tag
Humans MeSH
Male MeSH
Mice MeSH
Female MeSH
Animals MeSH
Publication type
Journal Article MeSH
Research Support, Non-U.S. Gov't MeSH
Names of Substances
ATF6 protein, human MeSH Browser
Benzamides MeSH
BRD4780 MeSH Browser
Heptanes MeSH
Imidazoline Receptors MeSH
RNA, Small Interfering MeSH
Mucin-1 MeSH
Bridged Bicyclo Compounds MeSH
NISCH protein, human MeSH Browser
TMED9 protein, human MeSH Browser
Activating Transcription Factor 6 MeSH
Vesicular Transport Proteins MeSH

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

Comment In

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