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

Vijayaraj, S.; Feltham, R.; Rashidi, M.; Frank, D.; Liu, Z.; Simpson, D.; Ebert, G.; Vince, A.; Herold, M. J.; Kueh, A. J.; Pearson, J.; Dagley, L.; Murphy, J. M.; Webb, A. I.; Lawlor, K. E.; Vince, J. E.

doi:10.1101/2021.03.15.435390

bioRxiv · 10.1101/2021.03.15.435390

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

Vijayaraj, S.·Feltham, R.·Rashidi, M.·Frank, D.·Liu, Z.·Simpson, D.·Ebert, G.·Vince, A.·Herold, M. J.·Kueh, A. J.·Pearson, J.·Dagley, L.·Murphy, J. M.·Webb, A. I.·Lawlor, K. E.·Vince, J. E.

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Abstract

Interleukin-1{beta} (IL-1{beta}) is activated by inflammasome-associated caspase-1 in rare autoinflammatory conditions and in wide-spread diseases. Therefore, IL-1{beta} activity must be fine-tuned to enable antimicrobial responses whilst limiting collateral damage. Here we report that precursor IL-1{beta} 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-1{beta} is not just a degradation signal triggered by inflammasome priming and activating stimuli, but also limits IL-1{beta} cleavage by caspase-1. We further demonstrate that IL-1{beta} K133 is modified by ubiquitin and forms a salt bridge with IL-1{beta} D129. Loss of IL-1{beta} K133 ubiquitylation, or disruption of the K133:D129 electrostatic interaction, stabilizes IL-1{beta}. Accordingly, IL-1{beta}K133R/K133R mice display increased precursor IL-1{beta} upon inflammasome priming and increased bioactive IL-1{beta}, both in vitro and following LPS injection in vivo. These findings reveal new mechanisms for limiting IL-1{beta} activity and safeguarding against damaging inflammation.

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Vijayaraj, S., Feltham, R., Rashidi, M., Frank, D., Liu, Z., Simpson, D., Ebert, G., Vince, A., Herold, M. J., Kueh, A. J., Pearson, J., Dagley, L., Murphy, J. M., Webb, A. I., Lawlor, K. E., Vince, J. E.. 2021-03-16. The inflammasome-activated cytokine IL-1 is targeted for ubiquitylation and proteasomal degradation to limit its inflammatory potential. https://doi.org/10.1101/2021.03.15.435390

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