PT  - JOURNAL ARTICLE
AU  - Swarna L. Vijayaraj
AU  - Rebecca Feltham
AU  - Maryam Rashidi
AU  - Daniel Frank
AU  - Zhengyang Liu
AU  - Daniel S. Simpson
AU  - Gregor Ebert
AU  - Angelina Vince
AU  - Marco J. Herold
AU  - Andrew Kueh
AU  - Jaclyn S. Pearson
AU  - Laura F. Dagley
AU  - James M. Murphy
AU  - Andrew I. Webb
AU  - Kate E. Lawlor
AU  - James E. Vince
TI  - The inflammasome-activated cytokine IL-1β is targeted for ubiquitylation and proteasomal degradation to limit its inflammatory potential
AID  - 10.1101/2021.03.15.435390
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.03.15.435390
4099  - http://biorxiv.org/content/early/2021/03/16/2021.03.15.435390.short
4100  - http://biorxiv.org/content/early/2021/03/16/2021.03.15.435390.full
AB  - Interleukin-1β (IL-1β) is activated by inflammasome-associated caspase-1 in rare autoinflammatory conditions and in wide-spread diseases. Therefore, IL-1β activity must be fine-tuned to enable antimicrobial responses whilst limiting collateral damage. Here we report that precursor IL-1β is rapidly turned over by the proteasome and this correlates with its decoration by K11-, K63- and K48-linked ubiquitin chains. The ubiquitylation of IL-1β is not just a degradation signal triggered by inflammasome priming and activating stimuli, but also limits IL-1β cleavage by caspase-1. We further demonstrate that IL-1β K133 is modified by ubiquitin and forms a salt bridge with IL-1β D129. Loss of IL-1β K133 ubiquitylation, or disruption of the K133:D129 electrostatic interaction, stabilizes IL-1β. Accordingly, IL-1βK133R/K133R mice display increased precursor IL-1β upon inflammasome priming and increased bioactive IL-1β, both in vitro and following LPS injection in vivo. These findings reveal new mechanisms for limiting IL-1β activity and safeguarding against damaging inflammation.Competing Interest StatementThe authors have declared no competing interest.