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A bacterial toxin co-opts caspase-3 to disable active gasdermin D and limit macrophage pyroptosis

Skylar S Wright1, Chengliang Wang1, Atri Ta2

  • 1Department of Immunology, UConn Health School of Medicine, 263 Farmington Avenue, Farmington, CT 06030, USA.

Cell Reports
|March 24, 2024
PubMed

Insights

Enterohemorrhagic Escherichia coli (EHEC) uses Shiga toxin to activate caspase-3, which inactivates gasdermin D (GSDMD) and inhibits pyroptosis. This reveals a novel bacterial immune evasion strategy targeting active GSDMD fragments.

Area of Science:

  • Immunology
  • Microbiology
  • Cell Biology

Background:

  • Host cells encounter pathogen-associated molecular patterns (PAMPs) and virulence factors during infection, triggering complex signaling pathways.
  • Interactions between these pathways determine the outcome of host-pathogen interactions.
  • Enterohemorrhagic Escherichia coli (EHEC) infection involves lipopolysaccharide (LPS) and Shiga toxin (Stx), activating distinct innate immune responses.

Purpose of the Study:

  • To elucidate the complex interplay between bacterial exotoxin- and PAMP-induced innate immune pathways during EHEC infection.
  • To investigate the functional interaction between caspase-11 and caspase-3 in response to LPS and Stx.
  • To uncover novel bacterial immune evasion mechanisms.

Main Methods:

  • Investigating caspase activation and function during EHEC infection.
  • Analyzing the cleavage of gasdermin D (GSDMD) by activated caspases.
  • Assessing the impact of these interactions on pyroptosis and interleukin-1β maturation.

Main Results:

  • Lipopolysaccharide (LPS)-activated caspase-11 cleaves full-length gasdermin D (GSDMD) into an active N-terminal fragment (NT-GSDMD).
  • Shiga toxin (Stx)-activated caspase-3 subsequently cleaves NT-GSDMD, rendering it nonfunctional.
  • This inactivation of NT-GSDMD inhibits pyroptosis and interleukin-1β maturation, representing a distinct immune evasion strategy.

Conclusions:

  • Bacterial toxins can subvert host innate immunity through sophisticated mechanisms.
  • EHEC employs Shiga toxin to activate caspase-3, which antagonizes caspase-11 activity by degrading active NT-GSDMD.
  • This pathway highlights a novel bacterial strategy to inhibit pyroptosis and IL-1β maturation by targeting active GSDMD.
Keywords:
CP: ImmunologyCP: MicrobiologyEHECShiga toxincaspase-11caspase-3enterohemorrhagic E. coligasdermin Dnoncanonical inflammasomepyroptosis

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