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Structural basis for the oligomerization-facilitated NLRP3 activation.

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|February 7, 2024
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The NACHT-, leucine-rich-repeat-, and pyrin domain-containing protein 3 (NLRP3) undergoes a structural transition to an open octamer, revealing its activation mechanism. This oligomeric cooperative activation is crucial for inflammasome assembly in human diseases.

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Area of Science:

  • Molecular Biology
  • Structural Biology
  • Immunology

Background:

  • The NACHT-, leucine-rich-repeat-, and pyrin domain-containing protein 3 (NLRP3) is a key sensor in innate immunity.
  • NLRP3 inflammasomes are implicated in various inflammation-driven human diseases.
  • The precise mechanism of NLRP3 activation, particularly its intermediate states, remains poorly understood.

Purpose of the Study:

  • To elucidate the structural basis of NLRP3 activation.
  • To investigate the role of oligomerization in NLRP3 function.
  • To understand the interaction between NLRP3 and its regulator NEK7.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was used to determine the structure of NLRP3.
  • Site-directed mutagenesis was employed to probe the function of specific interfaces.
  • Biochemical assays were performed to study NEK7/NLRP3 interactions.

Main Results:

  • The cryo-EM structure revealed NLRP3 forming an open octamer with a ~90° hinge rotation at the NACHT domain.
  • Mutations at the open octamer interfaces impaired IL-1β signaling, confirming their role in activation.
  • The centrosomal kinase NEK7 was shown to disrupt large NLRP3 oligomers, forming monomers/dimers as a prerequisite for inflammasome assembly.

Conclusions:

  • NLRP3 activation involves a cooperative, oligomeric mechanism.
  • The open octameric state is a critical intermediate in NLRP3 inflammasome assembly.
  • NEK7 plays a crucial role in initiating the NLRP3 activation cascade by destabilizing higher-order oligomers.