Structural basis for the oligomerization-facilitated NLRP3 activation

Xiaodi Yu (), Rosalie E. Matico, Robyn Miller, Dhruv Chauhan, Bertrand Schoubroeck, Karolien Grauwen, Javier Suarez, Beth Pietrak, Nandan Haloi, Yanting Yin, Gary John Tresadern, Laura Perez-Benito, Erik Lindahl, Astrid Bottelbergs, Daniel Oehlrich, Nina Opdenbosch and Sujata Sharma
Additional contact information
Xiaodi Yu: Johnson & Johnson Innovation Medicine
Rosalie E. Matico: Johnson & Johnson Innovation Medicine
Robyn Miller: Johnson & Johnson Innovation Medicine
Dhruv Chauhan: Johnson & Johnson Innovation Medicine, J&J Interventional Oncology
Bertrand Schoubroeck: Johnson & Johnson Innovation Medicine, J&J Interventional Oncology
Karolien Grauwen: Johnson & Johnson Innovation Medicine, J&J Interventional Oncology
Javier Suarez: Johnson & Johnson Innovation Medicine
Beth Pietrak: Johnson & Johnson Innovation Medicine
Nandan Haloi: Department of Applied Physics, Swedish e-Science Research Center, KTH Royal Institute of Technology
Yanting Yin: Johnson & Johnson Innovation Medicine
Gary John Tresadern: Johnson & Johnson Innovation Medicine, Discovery Sciences
Laura Perez-Benito: Johnson & Johnson Innovation Medicine, Discovery Sciences
Erik Lindahl: Stockholm University
Astrid Bottelbergs: Johnson & Johnson Innovation Medicine, Discovery Sciences
Daniel Oehlrich: Johnson & Johnson Innovation Medicine, Discovery Sciences
Nina Opdenbosch: Johnson & Johnson Innovation Medicine, J&J Interventional Oncology
Sujata Sharma: Johnson & Johnson Innovation Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-45396-8

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