IL-1β turnover by the UBE2L3 ubiquitin conjugating enzyme and HECT E3 ligases limits inflammation.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
20 07 2023
20 07 2023
Historique:
received:
03
12
2022
accepted:
10
07
2023
medline:
24
7
2023
pubmed:
21
7
2023
entrez:
20
7
2023
Statut:
epublish
Résumé
The cytokine interleukin-1β (IL-1β) has pivotal roles in antimicrobial immunity, but also incites inflammatory disease. Bioactive IL-1β is released following proteolytic maturation of the pro-IL-1β precursor by caspase-1. UBE2L3, a ubiquitin conjugating enzyme, promotes pro-IL-1β ubiquitylation and proteasomal disposal. However, actions of UBE2L3 in vivo and its ubiquitin ligase partners in this process are unknown. Here we report that deletion of Ube2l3 in mice reduces pro-IL-1β turnover in macrophages, leading to excessive mature IL-1β production, neutrophilic inflammation and disease following inflammasome activation. An unbiased RNAi screen identified TRIP12 and AREL1 E3 ligases of the Homologous to E6 C-terminus (HECT) family in adding destabilising K27-, K29- and K33- poly-ubiquitin chains on pro-IL-1β. We show that precursor abundance determines mature IL-1β production, and UBE2L3, TRIP12 and AREL1 limit inflammation by shrinking the cellular pool of pro-IL-1β. Our study uncovers fundamental processes governing IL-1β homeostasis and provides molecular insights that could be exploited to mitigate its adverse actions in disease.
Identifiants
pubmed: 37474493
doi: 10.1038/s41467-023-40054-x
pii: 10.1038/s41467-023-40054-x
pmc: PMC10359330
doi:
Substances chimiques
Interleukin-1beta
0
Ubiquitin
0
Ubiquitin-Conjugating Enzymes
EC 2.3.2.23
Ubiquitin-Protein Ligases
EC 2.3.2.27
Ube2l3 protein, mouse
EC 2.3.2.23
IL1B protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4385Subventions
Organisme : Medical Research Council
ID : MR/P022138/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/T00004X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/V030930/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P028225/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R502376/1
Pays : United Kingdom
Informations de copyright
© 2023. The Author(s).
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