Highlights d HDAC3 promotes IL-1b-dependent inflammation d HDAC3 restricts fatty acid oxidation for optimal NLRP3 inflammasome activation d HDAC3 translocates to mitochondria upon NLRP3 inflammasome activation d HDAC3 deacetylates HADHA at lysine 303 to restrain its enzyme activity

Goblet cells and their main secretory product, mucus, play crucial roles in orchestrating the colonic host-microbe interactions that help maintain gut homeostasis. However, the precise intracellular machinery underlying this goblet cell–induced mucus secretion remains poorly understood. Gasdermin D (GSDMD) is a recently identified pore-forming effector protein that causes pyroptosis, a lytic proinflammatory type of cell death occurring during various pathophysiological conditions. Here, we reveal an unexpected function of GSDMD in goblet cell mucin secretion and mucus layer formation. Specific deletion of Gsdmd in intestinal epithelial cells (Δ IEC ) led to abrogated mucus secretion with a concomitant loss of the mucus layer. This impaired colonic mucus layer in Gsdmd Δ IEC mice featured a disturbed host-microbial interface and inefficient clearance of enteric pathogens from the mucosal surface. Mechanistically, stimulation of goblet cells activates caspases to process GSDMD via reactive oxygen species production; in turn, this activated GSDMD drives mucin secretion through calcium ion–dependent scinderin-mediated cortical F-actin disassembly, which is a key step in granule exocytosis. This study links epithelial GSDMD to the secretory granule exocytotic pathway and highlights its physiological nonpyroptotic role in shaping mucosal homeostasis in the gut.

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