SERPINB1-mediated checkpoint of inflammatory caspase activation.
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Choi YJ, Kim S, Choi Y, Nielsen TB, Yan J, Lu A, Ruan J, Lee HR, Wu H, Spellberg B, Jung JU
SERPINB1-mediated checkpoint of inflammatory caspase activation.
Nat Immunol. 2019 Mar;20(3):276-287. doi: 10.1038/s41590-018-0303-z. Epub 2019 Jan 28.
- PubMed ID
- 30692621 [ View in PubMed]
- Abstract
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-1beta 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.