IL-1β turnover by the UBE2L3 ubiquitin conjugating enzyme and HECT E3 ligases limits inflammation

Vishwas Mishra, Anna Crespo-Puig, Callum McCarthy, Tereza Masonou, Izabela Glegola-Madejska, Alice Dejoux, Gabriella Dow, Matthew J. G. Eldridge, Luciano H. Marinelli, Meihan Meng, Shijie Wang, Daniel J. Bennison, Rebecca Morrison and Avinash R. Shenoy ()
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Vishwas Mishra: Department of Infectious Disease, Imperial College London
Anna Crespo-Puig: Department of Infectious Disease, Imperial College London
Callum McCarthy: Department of Infectious Disease, Imperial College London
Tereza Masonou: Department of Infectious Disease, Imperial College London
Izabela Glegola-Madejska: Department of Infectious Disease, Imperial College London
Alice Dejoux: Department of Infectious Disease, Imperial College London
Gabriella Dow: Department of Infectious Disease, Imperial College London
Matthew J. G. Eldridge: Department of Infectious Disease, Imperial College London
Luciano H. Marinelli: Department of Infectious Disease, Imperial College London
Meihan Meng: Department of Infectious Disease, Imperial College London
Shijie Wang: Department of Infectious Disease, Imperial College London
Daniel J. Bennison: Department of Infectious Disease, Imperial College London
Rebecca Morrison: The Francis Crick Institute
Avinash R. Shenoy: Department of Infectious Disease, Imperial College London

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-40054-x

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