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Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy

M. Dvela-Levitt, M. Kost-Alimova, M. Emani, E. Kohnert, R. Thompson, EH. Sidhom, A. Rivadeneira, N. Sahakian, J. Roignot, G. Papagregoriou, MS. Montesinos, AR. Clark, D. McKinney, J. Gutierrez, M. Roth, L. Ronco, E. Elonga, TA. Carter, A. Gnirke,...

. 2019 ; 178 (3) : 521-535.e23. [pub] 20190725

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc20023811

Grantová podpora
NV17-29786A MZ0 CEP - Centrální evidence projektů

Digitální knihovna NLK
Plný text - Článek

E-zdroje Online Plný text

NLK Cell Press Free Archives od 1995-01-01 do Před 1 rokem
Free Medical Journals od 1995 do Před 1 rokem
Open Access Digital Library od 1995-01-01
Elsevier Open Access Journals od 1995-01-13 do 2023-06-22
Elsevier Open Archive Journals od 1995-01-13 do Před 1 rokem

Odkazy

PubMed 31348885
DOI 10.1016/j.cell.2019.07.002
Knihovny.cz E-zdroje

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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