In this section
@article{Mishra:2022:10.1101/2022.09.14.507790,
author = {Mishra, V and Crespo-Puig, A and McCarthy, C and Masonou, T and Glegola-Madejska, I and Dejoux, A and Dow, G and Eldridge, MJG and Marinelli, LH and Meng, M and Wang, S and Bennison, DJ and Shenoy, AR},
doi = {10.1101/2022.09.14.507790},
title = {IL-1β turnover by TRIP12 and AREL1 ubiquitin ligases and UBE2L3 limits inflammation},
url = {http://dx.doi.org/10.1101/2022.09.14.507790},
year = {2022}
}
TY - JOUR
AB - <jats:title>ABSTRACT</jats:title><jats:p>The cytokine interleukin-1β (IL-1β) has pivotal roles in antimicrobial immunity, but also incites inflammatory pathology. Bioactive IL-1β is released following proteolytic maturation of the pro-IL-1β precursor by caspase-1 inflammasomes. UBE2L3/UBCH7, a conserved ubiquitin conjugating enzyme, promotes pro-IL-1β ubiquitylation and proteasomal disposal. However, UBE2L3 actions<jats:italic>in vivo</jats:italic>and ubiquitin ligases involved in this process are unknown. Here we report that deletion of<jats:italic>Ube2l3</jats:italic>in mice markedly reduces pro-IL-1β turnover in macrophages, leading to excessive mature IL-1β production, neutrophilic inflammation and disease symptoms following inflammasome activation. A family-wide siRNA screen identified two ubiquitin ligases, TRIP12 and AREL1, which we show add K27-, K29- and K33- poly-ubiquitin chains on lysine residues in the ‘pro’ domain and destabilise pro-IL-1β. Mutation of ubiquitylation sites increased pro-IL-1β stability, but did not affect proteolysis by caspase-1. The extent of mature IL-1β production is therefore determined by precursor abundance, and UBE2L3, TRIP12 and AREL1 limit inflammation by shrinking the cellular pool of pro-IL-1β. Our study has uncovered fundamental processes governing IL-1β homeostasis and provided molecular insights that could be exploited to mitigate its adverse actions in disease.</jats:p>
AU - Mishra,V
AU - Crespo-Puig,A
AU - McCarthy,C
AU - Masonou,T
AU - Glegola-Madejska,I
AU - Dejoux,A
AU - Dow,G
AU - Eldridge,MJG
AU - Marinelli,LH
AU - Meng,M
AU - Wang,S
AU - Bennison,DJ
AU - Shenoy,AR
DO - 10.1101/2022.09.14.507790
PY - 2022///
TI - IL-1β turnover by TRIP12 and AREL1 ubiquitin ligases and UBE2L3 limits inflammation
UR - http://dx.doi.org/10.1101/2022.09.14.507790
ER -
CBRB
Imperial College London
Flowers Building
Exhibition Road
London SW7 2AZ
