Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy

Moran Dvela-Levitt; Maria Kost-Alimova; Maheswarareddy Emani; Eva Kohnert; Rebecca Thompson; Eriene-Heidi Sidhom; Ana Rivadeneira; Nareh Sahakian; Julie Roignot; Gregory Papagregoriou; Monica S Montesinos; Abbe R Clark; David McKinney; Juan Gutierrez; Mark Roth; Lucienne Ronco; Esther Elonga; Todd A Carter; Andreas Gnirke; Michelle Melanson; Kate Hartland; Nicolas Wieder; Jane C-H Hsu; Constantinos Deltas; Rebecca Hughey; Anthony J Bleyer; Stanislav Kmoch; Martina Živná; Veronika Barešova; Savithri Kota; Johannes Schlondorff; Myriam Heiman; Seth L Alper; Florence Wagner; Astrid Weins; Todd R Golub; Eric S Lander; Anna Greka

doi:10.1016/j.cell.2019.07.002

Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy

Cell. 2019 Jul 25;178(3):521-535.e23. doi: 10.1016/j.cell.2019.07.002.

Authors

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

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Activating Transcription Factor 6 / metabolism
Animals
Benzamides / chemistry
Benzamides / metabolism*
Benzamides / pharmacology
Bridged Bicyclo Compounds / pharmacology*
Bridged Bicyclo Compounds / therapeutic use
Epithelial Cells / cytology
Epithelial Cells / metabolism
Female
Frameshift Mutation
Heptanes / pharmacology*
Heptanes / therapeutic use
Humans
Imidazoline Receptors / antagonists & inhibitors
Imidazoline Receptors / genetics
Imidazoline Receptors / metabolism
Induced Pluripotent Stem Cells / cytology
Induced Pluripotent Stem Cells / metabolism
Kidney / cytology
Kidney / metabolism
Kidney / pathology
Kidney Diseases / metabolism
Kidney Diseases / pathology
Lysosomes / drug effects*
Lysosomes / metabolism
Male
Mice
Mice, Transgenic
Mucin-1 / chemistry
Mucin-1 / genetics
Mucin-1 / metabolism
RNA Interference
RNA, Small Interfering / metabolism
Unfolded Protein Response / drug effects
Vesicular Transport Proteins / chemistry
Vesicular Transport Proteins / metabolism*

Substances

ATF6 protein, human
Activating Transcription Factor 6
BRD4780
Benzamides
Bridged Bicyclo Compounds
Heptanes
Imidazoline Receptors
Mucin-1
NISCH protein, human
RNA, Small Interfering
TMED9 protein, human
Vesicular Transport Proteins

Grants and funding

R01 DK099465/DK/NIDDK NIH HHS/United States