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

  • Nat Commun. 2021 May 11;12(1):2713. doi: 10.1038/s41467-021-22979-3.
Swarna L Vijayaraj   #  1  2 ,  Rebecca Feltham   #  1  2 ,  Maryam Rashidi  1  2 ,  Daniel Frank  1  2 ,  Zhengyang Liu  1 ,  Daniel S Simpson  1  2 ,  Gregor Ebert  1  2 ,  Angelina Vince  1 ,  Marco J Herold  1  2 ,  Andrew Kueh  1  2 ,  Jaclyn S Pearson  3  4  5 ,  Laura F Dagley  1  2 ,  James M Murphy  1  2 ,  Andrew I Webb  1  2 ,  Kate E Lawlor  6  7  8  9 ,  James E Vince  10  11
Affiliations
  • 1. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
  • 2. Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
  • 3. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
  • 4. Department of Microbiology, Monash University, Clayton, VIC, Australia.
  • 5. Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia.
  • 6. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. [email protected].
  • 7. Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia. [email protected].
  • 8. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia. [email protected].
  • 9. Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia. [email protected].
  • 10. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. [email protected].
  • 11. Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia. [email protected].
  • # Contributed equally.
PMID: 33976225 DOI: 10.1038/s41467-021-22979-3
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.

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