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

Author

Listed:
  • Swarna L. Vijayaraj

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Rebecca Feltham

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Maryam Rashidi

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Daniel Frank

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Zhengyang Liu

    (The Walter and Eliza Hall Institute of Medical Research)

  • Daniel S. Simpson

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Gregor Ebert

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Angelina Vince

    (The Walter and Eliza Hall Institute of Medical Research)

  • Marco J. Herold

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Andrew Kueh

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Jaclyn S. Pearson

    (Hudson Institute of Medical Research
    Monash University
    Monash University)

  • Laura F. Dagley

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • James M. Murphy

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Andrew I. Webb

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Kate E. Lawlor

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    Hudson Institute of Medical Research
    Monash University)

  • James E. Vince

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

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.

Suggested Citation

  • 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., 2021. "The ubiquitylation of IL-1β limits its cleavage by caspase-1 and targets it for proteasomal degradation," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22979-3
    DOI: 10.1038/s41467-021-22979-3
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