Auranofin targets UBA1 and enhances UBA1 activity by facilitating ubiquitin trans-thioesterification to E2 ubiquitin-conjugating enzymes.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
09 08 2023
09 08 2023
Historique:
received:
09
01
2023
accepted:
25
07
2023
medline:
11
8
2023
pubmed:
10
8
2023
entrez:
9
8
2023
Statut:
epublish
Résumé
UBA1 is the primary E1 ubiquitin-activating enzyme responsible for generation of activated ubiquitin required for ubiquitination, a process that regulates stability and function of numerous proteins. Decreased or insufficient ubiquitination can cause or drive aging and many diseases. Therefore, a small-molecule enhancing UBA1 activity could have broad therapeutic potential. Here we report that auranofin, a drug approved for the treatment of rheumatoid arthritis, is a potent UBA1 activity enhancer. Auranofin binds to the UBA1's ubiquitin fold domain and conjugates to Cys1039 residue. The binding enhances UBA1 interactions with at least 20 different E2 ubiquitin-conjugating enzymes, facilitating ubiquitin charging to E2 and increasing the activities of seven representative E3s in vitro. Auranofin promotes ubiquitination and degradation of misfolded ER proteins during ER-associated degradation in cells at low nanomolar concentrations. It also facilitates outer mitochondrial membrane-associated degradation. These findings suggest that auranofin can serve as a much-needed tool for UBA1 research and therapeutic exploration.
Identifiants
pubmed: 37558718
doi: 10.1038/s41467-023-40537-x
pii: 10.1038/s41467-023-40537-x
pmc: PMC10412574
doi:
Substances chimiques
Ubiquitin
0
Ubiquitin-Conjugating Enzymes
EC 2.3.2.23
Auranofin
3H04W2810V
Ubiquitin-Activating Enzymes
EC 6.2.1.45
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
4798Informations de copyright
© 2023. Springer Nature Limited.
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