Role of Gate-16 and Gabarap in Prevention of Caspase-11-Dependent Excess Inflammation and Lethal Endotoxic Shock

Naoya Sakaguchi, Miwa Sasai, Hironori Bando, Youngae Lee, Ariel Pradipta, Ji Su Ma, Masahiro Yamamoto

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Sepsis is a life-threating multi-organ disease induced by host innate immunity to pathogen-derived endotoxins including lipopolysaccharide (LPS). Direct sensing of LPS by caspase-11 activates inflammasomes and causes lethal sepsis in mice. Inhibition of caspase-11 inflammasomes is important for the prevention of LPS-induced septic shock; however, whether a caspase-11 inflammasome-specific suppressive mechanism exists is unclear. Here we show that deficiency of GABARAP autophagy-related proteins results in over-activation of caspase-11 inflammasomes but not of canonical inflammasomes. Gate-16−/−Gabarap−/− macrophages exhibited elevated guanylate binding protein 2 (GBP2)-dependent caspase-11 activation and inflammatory responses. Deficiency of GABARAPs resulted in formation of GBP2-containing aggregates that promote IL-1β production. High mortality after low dose LPS challenge in Gate-16−/−Gabarap−/− mice primed with poly(I:C) or polymicrobial sepsis was ameliorated by compound GBP2 deficiency. These results reveal a critical function of Gate-16 and Gabarap to suppress GBP2-dependent caspase-11-induced inflammation and septic shock.

Original languageEnglish
Article number561948
JournalFrontiers in immunology
Volume11
DOIs
Publication statusPublished - 2020 Sep 15
Externally publishedYes

Keywords

  • GBP2
  • Gate-16
  • caspase-11
  • non-canonical inflammasome
  • sepsis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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