The ubiquitylation of IL-1β limits its cleavage by caspase-1 and targets it for proteasomal degradation
Swarna Lekha Vijayaraj, Rebecca Feltham, Maryam Rashidi, Daniel Frank, Zhengyang Liu, Daniel S. Simpson, Gregor Ebert, Angelina J. Vince, Marco J. Herold, Andrew J. Kueh, Jaclyn S. Pearson, Laura F. Dagley, James M. Murphy, Andrew I. Webb, Kate E. Lawlor, James E. Vince
Abstract
Abstract Interleukin-1β (IL-1β) is activated by inflammasome-associated caspase-1 in rare autoinflammatory conditions and in a variety of other inflammatory diseases. Therefore, IL-1β activity must be fine-tuned to enable anti-microbial responses whilst limiting collateral damage. Here, we show that precursor IL-1β is rapidly turned over by the proteasome and this correlates with its decoration by K11-linked, K63-linked 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. 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, Il1b K133R/K133R mice have increased levels of precursor IL-1β upon inflammasome priming and increased production of bioactive IL-1β, both in vitro and in response to LPS injection. These findings identify mechanisms that can limit IL-1β activity and safeguard against damaging inflammation.