| First Author | Vijayaraj SL | Year | 2021 |
| Journal | Nat Commun | Volume | 12 |
| Issue | 1 | Pages | 2713 |
| PubMed ID | 33976225 | Mgi Jnum | J:306336 |
| Mgi Id | MGI:6713849 | Doi | 10.1038/s41467-021-22979-3 |
| Citation | Vijayaraj SL, et al. (2021) The ubiquitylation of IL-1beta limits its cleavage by caspase-1 and targets it for proteasomal degradation. Nat Commun 12(1):2713 |
| abstractText | Interleukin-1beta (IL-1beta) is activated by inflammasome-associated caspase-1 in rare autoinflammatory conditions and in a variety of other inflammatory diseases. Therefore, IL-1beta activity must be fine-tuned to enable anti-microbial responses whilst limiting collateral damage. Here, we show that precursor IL-1beta 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-1beta is not just a degradation signal triggered by inflammasome priming and activating stimuli, but also limits IL-1beta cleavage by caspase-1. IL-1beta K133 is modified by ubiquitin and forms a salt bridge with IL-1beta D129. Loss of IL-1beta K133 ubiquitylation, or disruption of the K133:D129 electrostatic interaction, stabilizes IL-1beta. Accordingly, Il1b(K133R/K133R) mice have increased levels of precursor IL-1beta upon inflammasome priming and increased production of bioactive IL-1beta, both in vitro and in response to LPS injection. These findings identify mechanisms that can limit IL-1beta activity and safeguard against damaging inflammation. |
