Endolysosomal damage surveillance enables rapid inflammasome sensing of pathogens

Abstract

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 galectin-8 exists in a complex with caspase-4 in naive cells and recruits caspase-4 to bacteria upon endolysosomal rupture, enabling lipopolysaccharide (LPS) sensing. Collectively, this study reveals galectin-8 as a hub integrating endomembrane damage sensing and inflammasome sensing. Thus, tethering the pathogen sensor caspase-4 to the endomembrane damage sensor galectin-8 poises the host to rapidly detect bacteria that breach the endolysosomal network.

Keywords: CP: Immunology; caspase-4; cell death; endolysosomes; galectins; gasdermin D; inflammasome; pathogen sensing; pyroptosis.