Imperial College London
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Avinash R. Shenoy

Faculty of Medicine, Department of Infectious Disease

Reader in Innate Immunity and Infection
 
 
 
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Contact

 

+44 (0)20 7594 3785a.shenoy Website

 
 
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Location

 

4.40AFlowers buildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@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}
}
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RIS format (EndNote, RefMan)

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  -
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