Journal Article

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

Marinelli, Luciano H., Dow, Gabriella, Shenoy, Avinash R., Morrison, Rebecca, Masonou, Tereza, Bennison, Daniel J., Meng, Meihan, Wang, Shijie, Crespo-Puig, Anna, Mishra, Vishwas, Dejoux, Alice, Glegola-Madejska, Izabela, Eldridge, Matthew J. G., McCarthy, Callum

2023

Overview

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. The turnover of interleukin-1β, a cytokine that plays important roles in both physiologic and pathologic inflammatory processes, is regulated by proteolytic maturation of the pro-form and by ubiquitin-mediated degradation. Here authors identify the specific ubiquitin E3 ligases that form an active complex with UBE2L3, a ubiquitin conjugating enzyme, that target pro-IL-1β for proteasomal breakdown.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/21 / 13/31 / 13/89 / 631/250/127/1216 / 631/250/256/2177 / 631/250/262 / 631/80/458/582 / 64 / 64/60 / 82/80 / 96 / 96/44 / Animals / C-Terminus / Caspase-1 / Cytokines / Enzymes / Homeostasis / Humanities and Social Sciences / IL-1β / Inflammasomes / Inflammation / Inflammatory diseases / Interleukin-1beta / Interleukins / Leukocytes (neutrophilic) / Macrophages / Maturation / Mice / multidisciplinary / Precursors / Proteasomes / Proteolysis / RNA-mediated interference / Science / Science (multidisciplinary) / Ubiquitin / Ubiquitin-conjugating enzyme / Ubiquitin-Conjugating Enzymes - genetics / Ubiquitin-protein ligase / Ubiquitin-Protein Ligases - genetics