2. Academic Validation
  3. The ubiquitylation of IL-1β limits its cleavage by caspase-1 and targets it for proteasomal degradation

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

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. kate.lawlor@hudson.org.au.
  • 7 Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia. kate.lawlor@hudson.org.au.
  • 8 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia. kate.lawlor@hudson.org.au.
  • 9 Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia. kate.lawlor@hudson.org.au.
  • 10 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. vince@wehi.edu.au.
  • 11 Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia. vince@wehi.edu.au.
  • # 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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