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Distinct sequential death complexes regulate pyroptosis and IL-1β release in response to Yersinia blockade of immune

Ronit Schwartz Wertman1, Winslow Yost1, Beatrice I Herrmann1

  • 1Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA.

Science Advances
|July 26, 2024
PubMed

Insights

Yersinia infection triggers a unique cell death pathway involving caspase-8 and caspase-1, distinct from typical inflammasome activation. This study uncovers novel mechanisms of pyroptosis and IL-1β release during pathogen-induced immune signaling blockade.

Area of Science:

  • Immunology
  • Cell Biology
  • Microbiology

Background:

  • Pathogen infection induces pyroptosis, an inflammatory cell death mediated by inflammatory caspases.
  • The Yersinia virulence factor YopJ disrupts immune signaling, leading to cell death involving both apoptotic caspase-8 and pyroptotic caspase-1.
  • Yersinia-induced caspase-1 activation bypasses canonical inflammasome pathways.

Purpose of the Study:

  • To elucidate the mechanisms of Yersinia-induced pyroptosis and IL-1β release.
  • To investigate the roles of caspase-8 and caspase-1 in Yersinia-mediated cell death.
  • To differentiate the pathways controlling pyroptosis and IL-1β secretion.

Main Methods:

  • Utilized Yersinia infection models in host cells.
  • Investigated caspase activation kinetics and localization.
  • Analyzed inflammasome component involvement (NLRP3) and gasdermin D activation.

Main Results:

  • Caspase-8 acts as an initiator, and caspase-1 amplifies its own activation via feed-forward loops.
  • Yersinia-induced pyroptosis and caspase-1 activation are inflammasome-independent.
  • IL-1β release, however, necessitates NLRP3 inflammasome activation.
  • Caspase-8 and canonical inflammasome complexes assemble distinctly in space and time.

Conclusions:

  • Yersinia employs distinct, interconnected death complexes to mediate pyroptosis and IL-1β release.
  • Caspase-8 initiates a novel cell death pathway, while caspase-1 amplifies it through auto-processing and gasdermin D activation.
  • Inflammasome-dependent and -independent pathways are differentially regulated for cell death and cytokine release.

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