NLRP3 inflammasome inhibition is disrupted in a group of auto-inflammatory disease CAPS mutations

Dysregulated inflammasome activation is associated with auto-inflammatory diseases. Chadee and colleagues show that prostaglandin E 2 triggers rapid inhibition of the inflammasome component NLRP3 by the kinase PKA. Patients with the inflammatory disease CAPS who have mutations in NLPR3 escape this negative regulation. Inflammasomes are positioned to rapidly escalate the intensity of inflammation by activating interleukin (IL)-1β, IL-18 and cell death by pyroptosis. However, negative regulation of inflammasomes remains poorly understood, as is the signaling cascade that dampens inflammasome activity. We found that rapid NLRP3 inflammasome activation was directly inhibited by protein kinase A (PKA), which was induced by prostaglandin E 2 (PGE 2 ) signaling via the PGE 2 receptor E-prostanoid 4 (EP4). PKA directly phosphorylated the cytoplasmic receptor NLRP3 and attenuated its ATPase function. We found that Ser295 in human NLRP3 was critical for rapid inhibition and PKA phosphorylation. Mutations in NLRP3 -encoding residues adjacent to Ser295 have been linked to the inflammatory disease CAPS (cryopyrin-associated periodic syndromes). NLRP3-S295A phenocopied the human CAPS mutants. These data suggest that negative regulation at Ser295 is critical for restraining the NLRP3 inflammasome and identify a molecular basis for CAPS-associated NLRP3 mutations.