A protein quality control pathway regulated by linear ubiquitination.
Adult
Aged
Animals
Brain
/ metabolism
Case-Control Studies
Cells, Cultured
Embryo, Mammalian
/ cytology
Female
Fibroblasts
/ cytology
Humans
Huntingtin Protein
/ genetics
Huntington Disease
/ genetics
Male
Mice
Mice, Knockout
Middle Aged
NF-kappa B
/ genetics
Neurons
/ metabolism
Polyubiquitin
/ metabolism
Protein Binding
Protein Interaction Domains and Motifs
Protein Processing, Post-Translational
Signal Transduction
Sp1 Transcription Factor
/ genetics
Ubiquitination
Valosin Containing Protein
/ genetics
LUBAC
OTULIN
Huntingtin
p97
protein aggregation
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
02 05 2019
02 05 2019
Historique:
received:
18
09
2018
revised:
12
02
2019
accepted:
13
02
2019
pubmed:
20
3
2019
medline:
7
1
2020
entrez:
20
3
2019
Statut:
ppublish
Résumé
Neurodegenerative diseases are characterized by the accumulation of misfolded proteins in the brain. Insights into protein quality control mechanisms to prevent neuronal dysfunction and cell death are crucial in developing causal therapies. Here, we report that various disease-associated protein aggregates are modified by the linear ubiquitin chain assembly complex (LUBAC). HOIP, the catalytic component of LUBAC, is recruited to misfolded Huntingtin in a p97/VCP-dependent manner, resulting in the assembly of linear polyubiquitin. As a consequence, the interactive surface of misfolded Huntingtin species is shielded from unwanted interactions, for example with the low complexity sequence domain-containing transcription factor Sp1, and proteasomal degradation of misfolded Huntingtin is facilitated. Notably, all three core LUBAC components are transcriptionally regulated by Sp1, linking defective LUBAC expression to Huntington's disease. In support of a protective activity of linear ubiquitination, silencing of OTULIN, a deubiquitinase with unique specificity for linear polyubiquitin, decreases proteotoxicity, whereas silencing of HOIP has the opposite effect. These findings identify linear ubiquitination as a protein quality control mechanism and hence a novel target for disease-modifying strategies in proteinopathies.
Identifiants
pubmed: 30886048
pii: embj.2018100730
doi: 10.15252/embj.2018100730
pmc: PMC6484417
pii:
doi:
Substances chimiques
HTT protein, human
0
Huntingtin Protein
0
NF-kappa B
0
Sp1 Transcription Factor
0
SP1 protein, human
0
Polyubiquitin
120904-94-1
Valosin Containing Protein
EC 3.6.4.6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2019 The Authors.
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