한빛사 논문
Youn Jung Choi1,2, Stephanie Kim1, Younho Choi1, Travis B. Nielsen1,3, Jun Yan1,3, Alvin Lu4,5, Jianbin Ruan4,5, Hye-Ra Lee6, Hao Wu4,5, Brad Spellberg1,3 and Jae U. Jung1,2,*
1Department 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.
*Correspondence to Jae U. Jung
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.
Publisher Correction: https://www.nature.com/articles/s41590-019-0361-x
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