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Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy.
- Source :
-
Cell [Cell] 2019 Jul 25; Vol. 178 (3), pp. 521-535.e23. - Publication Year :
- 2019
-
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.<br /> (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Subjects :
- Activating Transcription Factor 6 metabolism
Animals
Benzamides chemistry
Benzamides pharmacology
Bridged Bicyclo Compounds therapeutic use
Epithelial Cells cytology
Epithelial Cells metabolism
Female
Frameshift Mutation
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 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
Benzamides metabolism
Bridged Bicyclo Compounds pharmacology
Heptanes pharmacology
Lysosomes drug effects
Vesicular Transport Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4172
- Volume :
- 178
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cell
- Publication Type :
- Academic Journal
- Accession number :
- 31348885
- Full Text :
- https://doi.org/10.1016/j.cell.2019.07.002