Functional diversity of NLRP3 gain-of-function mutants associated with CAPS autoinflammation
NLRP3-associated autoinflammatory disease is a heterogenous group of monogenic conditions caused by NLRP3 gain-offunction
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-offunction
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.
