biostudies-literatureShivcharan SNIAID NIH HHS116002https://www.ebi.ac.uk/biostudies/studies/S-EPMC12871383biostudies-literatureUnknown44(8)Host cell cytosol is monitored by inflammasomes. Cytosolic invasion of pathogens involves breaching endolysosomal membranes, which is sensed by galectins triggering endolysosomal damage response. Whether and how endomembrane damage surveillance impacts inflammasome sensing of pathogens is unknown. Here, we show that endosomal damage sensing by galectin-8 licenses rapid noncanonical inflammasome sensing of intracellular bacteria; caspase-4 sensing of cytosol-invading bacteria, the consequent gasdermin D (GSDMD)-mediated pyroptosis, and interleukin (IL)-18 activation are greatly reduced in galectin-8-deficient human epithelial cells. Interestingly, galectin-8 promotes caspase-4 activation independently of the autophagic receptor NDP52 and bacterial restriction. Instead, we demonstrate that gCell reportsEndolysosomal damage surveillance enables rapid inflammasome sensing of pathogens.PMC12871383R01 AI148491R01 AI119015R01 AI132850R01 AI083359Shumba PFan ZWang CVanaja SKRathinam VADelgado KNAlto NMRuan JPanjwani NYounis DAChawla AKBehl BShivcharan SWright SSfalseEndolysosomal damage surveillance enables rapid inflammasome sensing of pathogens.Host cell cytosol is monitored by inflammasomes. Cytosolic invasion of pathogens involves breaching endolysosomal membranes, which is sensed by galectins triggering endolysosomal damage response. Whether and how endomembrane damage surveillance impacts inflammasome sensing of pathogens is unknown. Here, we show that endosomal damage sensing by galectin-8 licenses rapid noncanonical inflammasome sensing of intracellular bacteria; caspase-4 sensing of cytosol-invading bacteria, the consequent gasdermin D (GSDMD)-mediated pyroptosis, and interleukin (IL)-18 activation are greatly reduced in galectin-8-deficient human epithelial cells. Interestingly, galectin-8 promotes caspase-4 activation independently of the autophagic receptor NDP52 and bacterial restriction. Instead, we demonstrate that g2025-01-01T00:00:00Z2025 Aug2026-07-15T13:24:16.48Z2026-07-05T03:08:18.584ZS-EPMC128713834066867510.1016/j.celrep.2025.116002