Functional diversity of <i>NLRP3</i> gain-of-function mutants associated with CAPS autoinflammation
Camille Cosson, Romane Riou, Danish Patoli, Tingting Niu, Amaury Rey, Marine Groslambert, Charlotte de Rosny, Elodie Chatre, Omran Allatif, Thomas Henry, Fabienne Venet, Florian Milhavet, Guilaine Boursier, Alexandre Bélot, Yvan Jamilloux, Étienne Merlin, A. Duquesne, Gilles Grateau, Léa Savey, A. Maria, Anne Pagnier, Solène Poutrel, Olivier Lambotte, Coralie Mallebranche, Samuel Ardois, Olivier Richer, I. Lemelle, Frédéric Rieux‐Laucat, Brigitte Bader‐Meunier, Zahir Amoura, Isabelle Melki, Laurence Cuisset, Isabelle Touitou, Matthias Geyer, Sophie Georgin‐Lavialle, Bénédicte F. Py
Abstract
NLRP3-associated autoinflammatory disease is a heterogenous group of monogenic conditions caused by NLRP3 gain-of-function mutations. The poor functional characterization of most NLRP3 variants hinders diagnosis despite efficient anti-IL-1 treatments. Additionally, while NLRP3 is controlled by priming and activation signals, gain-of-functions have only been investigated in response to priming. Here, we characterize 34 NLRP3 variants in vitro, evaluating their activity upon induction, priming, and/or activation signals, and their sensitivity to four inhibitors. We highlight the functional diversity of the gain-of-function mutants and describe four groups based on the signals governing their activation, correlating partly with the symptom severity. We identify a new group of NLRP3 mutants responding to the activation signal without priming, associated with frequent misdiagnoses. Our results identify key NLRP3 residues controlling inflammasome activity and sensitivity to inhibitors, and antagonistic mechanisms with broader efficacy for therapeutic strategies. They provide new insights into NLRP3 activation, an explanatory mechanism for NLRP3-AID heterogeneity, and original tools for NLRP3-AID diagnosis and drug development.