NLRP3 phosphorylation in its LRR domain critically regulates inflammasome assembly - Archive ouverte HAL Access content directly
Journal Articles Nature Communications Year : 2021

NLRP3 phosphorylation in its LRR domain critically regulates inflammasome assembly

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Maggy Hologne
Olivier Walker

Abstract

Abstract NLRP3 controls the secretion of inflammatory cytokines IL-1β/18 and pyroptosis by assembling the inflammasome. Upon coordinated priming and activation stimuli, NLRP3 recruits NEK7 within hetero-oligomers that nucleate ASC and caspase-1 filaments, but the apical molecular mechanisms underlying inflammasome assembly remain elusive. Here we show that NEK7 recruitment to NLRP3 is controlled by the phosphorylation status of NLRP3 S803 located within the interaction surface, in which NLRP3 S803 is phosphorylated upon priming and later dephosphorylated upon activation. Phosphomimetic substitutions of S803 abolish NEK7 recruitment and inflammasome activity in macrophages in vitro and in vivo. In addition, NLRP3-NEK7 binding is also essential for NLRP3 deubiquitination by BRCC3 and subsequently inflammasome assembly, with NLRP3 phosphomimetic mutants showing enhanced ubiquitination and degradation than wildtype NLRP3. Finally, we identify CSNK1A1 as the kinase targeting NLRP3 S803. Our findings thus reveal NLRP3 S803 phosphorylation status as a druggable apical molecular mechanism controlling inflammasome assembly.
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Origin : Publication funded by an institution

Dates and versions

hal-03401509 , version 1 (24-11-2022)

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Tingting Niu, Charlotte de Rosny, Séverine Chautard, Amaury Rey, Danish Patoli, et al.. NLRP3 phosphorylation in its LRR domain critically regulates inflammasome assembly. Nature Communications, 2021, 12 (1), pp.Article number: 5862. ⟨10.1038/s41467-021-26142-w⟩. ⟨hal-03401509⟩
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