BPTES inhibits anthrax lethal toxin-induced inflammatory response

Int Immunopharmacol. 2020 Aug:85:106664. doi: 10.1016/j.intimp.2020.106664. Epub 2020 Jun 7.

Abstract

Bacillus anthracis is a lethal agent of anthrax disease and the toxins are required in anthrax pathogenesis. The anthrax lethal toxin can trigger NLRP1b inflammasome activation and pyroptosis. Although the underlying mechanism is well understood, the medications targeting the NLRP1b inflammasome are not available in the clinic. Herein, we describe that BPTES, a known Glutaminase (GLS) inhibitor, is an effective NLRP1b inflammasome inhibitor. BPTES could effectively and specifically suppress NLRP1b inflammasome activation in macrophages but have no effects on NLRP3, NLRC4 and AIM2 inflammasome activation. Mechanistically, BPTES alleviated the UBR2 mediated proteasomal degradation pathway of the NLRP1b N terminus, thus blocking the release of the CARD domain for subsequent caspase-1 processing. Furthermore, BPTES could prevent disease progression in mice challenged with the anthrax lethal toxin. Taken together, our studies indicate that BPTES can be a promising pharmacological inhibitor to treat anthrax lethal toxin-related inflammatory diseases.

Keywords: Anthrax lethal toxin; BPTES; Inflammatory response; NLRP1b.

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use*
  • Antigens, Bacterial / toxicity*
  • Apoptosis Regulatory Proteins / antagonists & inhibitors*
  • Bacterial Toxins / toxicity*
  • Cell Line
  • Female
  • Humans
  • Inflammasomes / antagonists & inhibitors*
  • Mice, Inbred BALB C
  • Sulfides / pharmacology
  • Sulfides / therapeutic use*
  • Thiadiazoles / pharmacology
  • Thiadiazoles / therapeutic use*

Substances

  • Adaptor Proteins, Signal Transducing
  • Anti-Inflammatory Agents
  • Antigens, Bacterial
  • Apoptosis Regulatory Proteins
  • Bacterial Toxins
  • Inflammasomes
  • NALP1 protein, mouse
  • Sulfides
  • Thiadiazoles
  • anthrax toxin
  • bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide