SERPINB1-mediated checkpoint of inflammatory caspase activation

  • Nat Immunol. 2019 Mar;20(3):276-287. doi: 10.1038/s41590-018-0303-z.
Youn Jung Choi  1  2 ,  Stephanie Kim  1 ,  Younho Choi  1 ,  Travis B Nielsen  1  3 ,  Jun Yan  1  3 ,  Alvin Lu  4  5 ,  Jianbin Ruan  4  5 ,  Hye-Ra Lee  6 ,  Hao Wu  4  5 ,  Brad Spellberg  1  3 ,  Jae U Jung  7  8
Affiliations
  • 1. Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 2. Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
  • 3. Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 4. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 5. Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
  • 6. Department of Biotechnology and Bioinformatics, Collage of Science and Technology, Korea University, Sejong, South Korea.
  • 7. Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. [email protected].
  • 8. Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA. [email protected].
PMID: 30692621 DOI: 10.1038/s41590-018-0303-z
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-1β 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.