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Nat Immunol. 2016 Oct;17(10):1176-86. doi: 10.1038/ni.3538. Epub 2016 Aug 22.

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

Author information

1
Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
2
Department of Biochemistry and Molecular Biology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Abstract

Inflammasomes are positioned to rapidly escalate the intensity of inflammation by activating interleukin (IL)-1╬▓, 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 E2 (PGE2) signaling via the PGE2 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.

PMID:
27548431
DOI:
10.1038/ni.3538
[Indexed for MEDLINE]

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