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Yu X, Matico RE, Miller R, Chauhan D, Van Schoubroeck B, Grauwen K, Suarez J, Pietrak B, Haloi N, Yin Y, Tresadern GJ, Perez-Benito L, Lindahl E, Bottelbergs A, Oehlrich D, Van Opdenbosch N, Sharma S
Nat Commun 15 (1) 1164 [2024-02-07; online 2024-02-07]
The NACHT-, leucine-rich-repeat-, and pyrin domain-containing protein 3 (NLRP3) is a critical intracellular inflammasome sensor and an important clinical target against inflammation-driven human diseases. Recent studies have elucidated its transition from a closed cage to an activated disk-like inflammasome, but the intermediate activation mechanism remains elusive. Here we report the cryo-electron microscopy structure of NLRP3, which forms an open octamer and undergoes a ~ 90° hinge rotation at the NACHT domain. Mutations on open octamer's interfaces reduce IL-1β signaling, highlighting its essential role in NLRP3 activation/inflammasome assembly. The centrosomal NIMA-related kinase 7 (NEK7) disrupts large NLRP3 oligomers and forms NEK7/NLRP3 monomers/dimers which is a critical step preceding the assembly of the disk-like inflammasome. These data demonstrate an oligomeric cooperative activation of NLRP3 and provide insight into its inflammasome assembly mechanism.
PubMed 38326375
DOI 10.1038/s41467-024-45396-8
Crossref 10.1038/s41467-024-45396-8
pmc: PMC10850481
pii: 10.1038/s41467-024-45396-8
PDB: 8SWK
PDB: 8SXN
PDB: 8SWF