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.
Show 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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