4.7 Article

SERPINB1-mediated checkpoint of inflammatory caspase activation

Journal

NATURE IMMUNOLOGY
Volume 20, Issue 3, Pages 276-+

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/s41590-018-0303-z

Keywords

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Categories

Funding

  1. [CA180779]
  2. [CA200422]
  3. [AI073099]
  4. [AI116585]
  5. [AI129496]
  6. [AI140718]
  7. [AI140705]
  8. [DE023926]
  9. [DE027888]
  10. [DE028521]
  11. [NRF-2016R1D1A1B03931761]
  12. [Al124491]
  13. [HD087988]
  14. [AI081719]
  15. [AI117211]
  16. [AI127954]
  17. [AI106375]

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Inflammatory caspases (caspase-1, caspase-4, caspase-5 and caspase-11 (caspase-1/-4/-5/-11)) mediate host defense against microbial infections, processing pro-inflammatory cytokines and triggering pyroptosis. However, precise checkpoints are required to prevent their unsolicited activation. Here we report that serpin family B member 1 (SERPINB1) limited the activity of those caspases by suppressing their caspase-recruitment domain (CARD) oligomerization and enzymatic activation. While the reactive center loop of SERPINB1 inhibits neutrophil serine proteases, its carboxy-terminal CARD-binding motif restrained the activation of pro-caspase-1/-4/-5/-11. Consequently, knockdown or deletion of SERPINB1 prompted spontaneous activation of caspase-1/-4/-5/-11, release of the cytokine IL-1 beta and pyroptosis, inducing elevated inflammation after non-hygienic co-housing with pet-store mice and enhanced sensitivity to lipopolysaccharide- or Acinetobacter baumannii-induced endotoxemia. Our results reveal that SERPINB1 acts as a vital gatekeeper of inflammation by restraining neutrophil serine proteases and inflammatory caspases in a genetically and functionally separable manner.

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