Endolysosomal damage surveillance enables rapid inflammasome sensing of pathogens

Area of Science:

• Cellular Microbiology
• Immunology
• Molecular Biology

Background:

• Inflammasomes monitor host cell cytosol for pathogens.
• Galectins detect endolysosomal membrane damage during pathogen invasion.
• The interplay between endomembrane damage sensing and inflammasome activation remains unclear.

Purpose of the Study:

• To investigate the role of endomembrane damage sensing in inflammasome activation against intracellular bacteria.
• To elucidate the mechanism by which galectin-8 influences noncanonical inflammasome sensing.

Main Methods:

• Utilized galectin-8-deficient human epithelial cells.
• Assessed caspase-4 activation, gasdermin D (GSDMD)-mediated pyroptosis, and interleukin (IL)-18 activation.
• Investigated the interaction between galectin-8 and caspase-4 using co-complex formation and recruitment assays.

Main Results:

• Galectin-8 deficiency significantly reduced inflammasome sensing of intracellular bacteria, including caspase-4 activation, pyroptosis, and IL-18 release.
• Galectin-8 promotes caspase-4 activation independently of NDP52 and bacterial restriction.
• Galectin-8 forms a complex with caspase-4 and recruits it to bacteria upon endolysosomal rupture, facilitating lipopolysaccharide (LPS) sensing.

Conclusions:

• Galectin-8 acts as a crucial link between endomembrane damage surveillance and inflammasome sensing.
• The galectin-8-caspase-4 complex enables rapid host detection of bacteria breaching the endolysosomal network.
• This integrated sensing mechanism enhances host defense against intracellular bacterial pathogens.