Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy.

Activating Transcription Factor 6 / metabolism Animals Benzamides / chemistry Bridged Bicyclo Compounds / pharmacology Epithelial Cells / cytology Female Frameshift Mutation Heptanes / pharmacology Humans Imidazoline Receptors / antagonists & inhibitors Induced Pluripotent Stem Cells / cytology Kidney / cytology Kidney Diseases / metabolism Lysosomes / drug effects Male Mice Mice, Transgenic Mucin-1 / chemistry RNA Interference RNA, Small Interfering / metabolism Unfolded Protein Response / drug effects Vesicular Transport Proteins / chemistry
COP vesicles ER stress Golgi apparatus cargo receptor endoplasmic reticulum epithelial cells kidney organoids secretory pathway unfolded protein response

Journal

Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066

Informations de publication

Date de publication:
25 07 2019
Historique:
received: 06 08 2018
revised: 19 04 2019
accepted: 28 06 2019
entrez: 27 7 2019
pubmed: 28 7 2019
medline: 28 4 2020
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.cell.2019.07.002 PMID: 31348885
pubmed: 31348885
pii: S0092-8674(19)30741-X
doi: 10.1016/j.cell.2019.07.002
pii:
doi:

Substances chimiques

ATF6 protein, human 0
Activating Transcription Factor 6 0
BRD4780 0
Benzamides 0
Bridged Bicyclo Compounds 0
Heptanes 0
Imidazoline Receptors 0
Mucin-1 0
NISCH protein, human 0
RNA, Small Interfering 0
TMED9 protein, human 0
Vesicular Transport Proteins 0

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

521-535.e23

Subventions

Organisme : NIDDK NIH HHS
ID : R01 DK099465
Pays : United States

Commentaires et corrections

Type : CommentIn
Type : CommentIn
Type : CommentIn

Informations de copyright

Copyright © 2019 Elsevier Inc. All rights reserved.

Auteurs

Moran Dvela-Levitt (M)

Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Maria Kost-Alimova (M)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Maheswarareddy Emani (M)

Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Eva Kohnert (E)

Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Rebecca Thompson (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.

Eriene-Heidi Sidhom (EH)

Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Ana Rivadeneira (A)

Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Nareh Sahakian (N)

Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Julie Roignot (J)

Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Gregory Papagregoriou (G)

Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus.

Monica S Montesinos (MS)

Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Abbe R Clark (AR)

Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

David McKinney (D)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Juan Gutierrez (J)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Mark Roth (M)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Lucienne Ronco (L)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Esther Elonga (E)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Todd A Carter (TA)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Andreas Gnirke (A)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Michelle Melanson (M)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Kate Hartland (K)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Nicolas Wieder (N)

Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Jane C-H Hsu (JC)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Constantinos Deltas (C)

Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus.

Rebecca Hughey (R)

Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Anthony J Bleyer (AJ)

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.

Stanislav Kmoch (S)

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.

Martina Živná (M)

Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.

Veronika Barešova (V)

Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.

Savithri Kota (S)

Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.

Johannes Schlondorff (J)

Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.

Myriam Heiman (M)

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.

Seth L Alper (SL)

Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.

Florence Wagner (F)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Astrid Weins (A)

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.

Todd R Golub (TR)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Eric S Lander (ES)

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.

Anna Greka (A)

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.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif basique et à glissière à leucines › Facteurs de transcription ATF › Facteur de transcription ATF-6 › Small Molecule Targets TMED9 and Promotes...
questionsmedicales.fr › Eucaryotes › Animaux › Small Molecule Targets TMED9 and Promotes...
questionsmedicales.fr › Composés chimiques organiques › Hydrocarbures › Hydrocarbures cycliques › Hydrocarbures aromatiques › Dérivés du benzène › Benzoates › Benzamides › Small Molecule Targets TMED9 and Promotes...
questionsmedicales.fr › Composés polycycliques › Composés pontés › Composés bicycliques pontés › Small Molecule Targets TMED9 and Promotes...
questionsmedicales.fr › Cellules › Cellules épithéliales › Small Molecule Targets TMED9 and Promotes...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation avec décalage du cadre de lecture › Small Molecule Targets TMED9 and Promotes...
questionsmedicales.fr › Composés chimiques organiques › Hydrocarbures › Hydrocarbures acycliques › Alcanes › Heptanes › Small Molecule Targets TMED9 and Promotes...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Small Molecule Targets TMED9 and Promotes...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Récepteurs des médicaments › Récepteurs des imidazolines › Small Molecule Targets TMED9 and Promotes...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches pluripotentes › Cellules souches pluripotentes induites › Small Molecule Targets TMED9 and Promotes...
questionsmedicales.fr › Appareil urogénital › Voies urinaires › Rein › Small Molecule Targets TMED9 and Promotes...
questionsmedicales.fr › Maladies urogénitales › Maladies urologiques › Maladies du rein › Small Molecule Targets TMED9 and Promotes...
questionsmedicales.fr › Cellules › Structures cellulaires › Espace intracellulaire › Cytoplasme › Structures cytoplasmiques › Organites › Vésicules cytoplasmiques › Lysosomes › Small Molecule Targets TMED9 and Promotes...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Small Molecule Targets TMED9 and Promotes...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Small Molecule Targets TMED9 and Promotes...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Marqueurs biologiques tumoraux › Antigènes glycanniques associés aux tumeurs › Mucine-1 › Small Molecule Targets TMED9 and Promotes...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › Extinction de l'expression des gènes › Interférence par ARN › Small Molecule Targets TMED9 and Promotes...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN non traduit › Petit ARN non traduit › Petit ARN interférent › Small Molecule Targets TMED9 and Promotes...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Modification traductionnelle des protéines › Maturation post-traductionnelle des protéines › Réponse aux protéines mal repliées › Small Molecule Targets TMED9 and Promotes...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines du transport vésiculaire › Small Molecule Targets TMED9 and Promotes...