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Caging NLRP3 tames inflammasome activity

Kate Schroder1, Rebecca C Coll2

  • 1Institute for Molecular Bioscience and IMB Centre for Inflammation and Disease Research, The University of Queensland, St. Lucia, QLD 4072, Australia.

Cell
|December 23, 2021
PubMed

Insights

The NLRP3 inflammasome, a key danger sensor, is regulated by a novel double-ring structure. This inactive form shields pyrin domains, revealing a new mechanism for inflammasome control.

Area of Science:

  • Immunology
  • Molecular Biology
  • Structural Biology

Background:

  • The activation mechanism of the NLRP3 inflammasome, a critical component of innate immunity, remains incompletely understood.
  • NLRP3 inflammasome activation is implicated in various inflammatory diseases.

Purpose of the Study:

  • To elucidate the structural basis of inactive NLRP3 inflammasome.
  • To uncover the mechanism regulating NLRP3 inflammasome activation.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was employed to determine the structure of inactive NLRP3.
  • Biochemical and structural analyses were performed.

Main Results:

  • Inactive NLRP3 forms a stable double ring composed of 12-16 monomers.
  • This double-ring structure sequesters the pyrin domains, preventing spontaneous inflammasome assembly.
  • Cryo-EM revealed the precise architecture of the inactive complex.

Conclusions:

  • NLRP3 inflammasome activation is regulated by a previously unrecognized double-ring inhibitory mechanism.
  • This discovery provides new insights into inflammasome assembly and regulation.
  • The findings offer potential targets for therapeutic intervention in NLRP3-associated inflammatory conditions.

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