The ubiquitylation of IL-1β limits its cleavage by caspase-1 and targets it for proteasomal degradation

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, Il1bK133R/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.

NLRP3 Ubiquitination—A New Approach to Target NLRP3 Inflammasome Activation

“…The study showed that the ubiquitination of pro-IL-1β limits the cellular level of pro-IL-1β by promoting its proteasomal degradation. Moreover, the ubiquitination inhibited IL-1β release through interfering with the caspase-1-mediated pro-IL-1β cleavage [136]. These results indicate that the ubiquitination of pro-IL-1β may play a role in limiting IL-1β level and caspase-1-mediated activation, which is contrary to previous studies.…”

“…However, a more recent study suggested that K133 ubiquitination of pro-IL-1β can limit inflammasome activation [136]. The study showed that the ubiquitination of pro-IL-1β limits the cellular level of pro-IL-1β by promoting its proteasomal degradation.…”

Delicate regulation of IL-1β-mediated inflammation by cyclophilin A

“…It is well accepted that K63-linked ubiquitination of pro-IL-1b is critical for inflammasome activation and IL-1b secretion (Duong et al, 2015;Vijayaraj et al, 2021). We therefore determined whether CypA influences the ubiquitination of pro-IL-1b.…”

PHOrming the inflammasome: phosphorylation is a critical switch in inflammasome signalling

“…Cleavage of IL-1β, IL-18, and GSDMD represent the final step of inflammasome activation [ 92 ]. IL-1β has one described phosphorylation site at Ser134, but its functional significance remains unknown as mutation of Ser134 did not affect the stability or secretion of IL-1β [ 93 ]. No direct phosphorylations have been described for IL-18, but both IL-1β and IL-18 are subject to significant regulation as they are transcribed as inactive pro-forms that require enzymatic cleavage for activation.…”

“…No direct phosphorylations have been described for IL-18, but both IL-1β and IL-18 are subject to significant regulation as they are transcribed as inactive pro-forms that require enzymatic cleavage for activation. They are also regulated by other PTMs, such as ubiquitylation [ 93 ]. GSDMD is the executioner of pyroptosis and to date has not been found to be directly phosphorylated [ 94 ].…”