Journal article

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

Swarna L Vijayaraj, Rebecca Feltham, Maryam Rashidi, Daniel Frank, Zhengyang Liu, Daniel S Simpson, Gregor Ebert, Angelina Vince, Marco J Herold, Andrew Kueh, Jaclyn S Pearson, Laura F Dagley, James M Murphy, Andrew I Webb, Kate E Lawlor, James E Vince

NATURE COMMUNICATIONS | NATURE RESEARCH | Published : 2021

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-..

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Grants

Awarded by National Health and Medical Research Council (NHMRC) of Australia


Awarded by Australian NHMRC Career Development Fellowship


Awarded by Leukemia and Lymphoma Society SCOR


Awarded by Australian Government Independent Research Institute Infrastructure Support Scheme



Funding Acknowledgements

We gratefully acknowledge grant support from the National Health and Medical Research Council (NHMRC) of Australia: project grants (1145788 to J.E.V., K.E.L. and J. M.M.; 1101405 to J.E.V.; 1162765 to K.E.L.), Ideas grants (1183070 to J.E.V.; 1181089 to K.E.L.) and fellowships (1172929 to J.M.M.; 1141466 to J.E.V.). K.E.L. is an Australian Research Council (ARC) Future Fellow (FT190100266). J.S.P. is supported by an Australian NHMRC Career Development Fellowship (1159230). MJH is and NHMRC Senior Research Fellow (1156095) and supported by the Leukemia and Lymphoma Society SCOR grant 7015-18. The generation of the Il1b K133R/K133R mice used in this study was supported by the Phenomics Australia (PA) and the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. This work was also supported by operational infrastructure grants through the Australian Government Independent Research Institute Infrastructure Support Scheme (9000653) and the Victorian State Government Operational Infrastructure Support, Australia.