Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy

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

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
² Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus.
⁴ Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁵ 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.
⁶ Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.
⁷ Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
⁸ 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.
⁹ 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.
¹⁰ 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.
¹¹ 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.

PMID: 31348885
DOI: 10.1016/j.cell.2019.07.002

Free article

Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy

Moran Dvela-Levitt et al. Cell. 2019.

Free article

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

doi: 10.1016/j.cell.2019.07.002.

Authors

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
² Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus.
⁴ Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁵ 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.
⁶ Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.
⁷ Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
⁸ 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.
⁹ 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.
¹⁰ 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.
¹¹ 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.

PMID: 31348885
DOI: 10.1016/j.cell.2019.07.002

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.

Keywords: COP vesicles; ER stress; Golgi apparatus; cargo receptor; endoplasmic reticulum; epithelial cells; kidney; organoids; secretory pathway; unfolded protein response.

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Comment in

Study of ADTKD-MUC1 identifies a new lead for the treatment of toxic proteinopathies.
Carney EF. Carney EF. Nat Rev Nephrol. 2019 Oct;15(10):593. doi: 10.1038/s41581-019-0194-8. Nat Rev Nephrol. 2019. PMID: 31388128 No abstract available.
A novel approach to reverse proteinopathies.
Otto G. Otto G. Nat Rev Drug Discov. 2019 Sep;18(9):665. doi: 10.1038/d41573-019-00133-5. Nat Rev Drug Discov. 2019. PMID: 31477861 No abstract available.
Pharmacological Correction of Proteinopathies via Lysosomal Degradation.
Jones LH. Jones LH. Biochemistry. 2020 Feb 18;59(6):727-728. doi: 10.1021/acs.biochem.9b00942. Epub 2020 Jan 30. Biochemistry. 2020. PMID: 31999102 No abstract available.

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Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy

Affiliations

Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy

Authors

Affiliations

Abstract

Comment in

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases

Research Materials

Miscellaneous