The inflammasome-activated cytokine IL-1β is targeted for ubiquitylation and proteasomal degradation to limit its inflammatory potential

Abstract

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.