The ubiquitylation of IL-1β limits its cleavage by caspase-1 and targets it for proteasomal degradation
- Vijayaraj, SL; Feltham, R; Rashidi, M; Frank, D; LIU, Z; Simpson, DS; Ebert, G; Vince, A; Herold, MJ; Kueh, A; Pearson, JS; Dagley, LF; Murphy, JM; Webb, AI; Lawlor, KE; Vince, JE;
Publication Year 2021-05-11, Volume 12, Issue #1, Page 2713
- Journal Title
- Nature Communications
- 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.
- WEHI Research Division(s)
- Infectious Diseases And Immune Defence; Blood Cells And Blood Cancer; Advanced Technology And Biology; Inflammation
- PubMed ID
- Publisher's Version
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- Refer to copyright notice on published article.
Creation Date: 2021-05-17 11:04:14Last Modified: 2021-05-17 11:53:44