NLRP3 phosphorylation in its LRR domain critically regulates inflammasome assembly

Tingting Niu, Charlotte Rosny, Séverine Chautard, Amaury Rey, Danish Patoli, Marine Groslambert, Camille Cosson, Brice Lagrange, Zhirong Zhang, Orane Visvikis, Sabine Hacot, Maggy Hologne, Olivier Walker, Jeimin Wong, Ping Wang, Roméo Ricci, Thomas Henry, Laurent Boyer, Virginie Petrilli and Bénédicte F. Py ()
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Tingting Niu: Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon
Charlotte Rosny: Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon
Séverine Chautard: Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon
Amaury Rey: Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon
Danish Patoli: Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon
Marine Groslambert: Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon
Camille Cosson: Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon
Brice Lagrange: Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon
Zhirong Zhang: CNRS, UMR7104, Inserm, U964, Université de Strasbourg
Orane Visvikis: Université Côte d’Azur, Inserm, C3M
Sabine Hacot: INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon Bérard
Maggy Hologne: Univ Lyon, CNRS, CNRS UMR5280, Université Claude Bernard Lyon 1
Olivier Walker: Univ Lyon, CNRS, CNRS UMR5280, Université Claude Bernard Lyon 1
Jeimin Wong: East China Normal University
Ping Wang: Tongji University
Roméo Ricci: CNRS, UMR7104, Inserm, U964, Université de Strasbourg
Thomas Henry: Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon
Laurent Boyer: Université Côte d’Azur, Inserm, C3M
Virginie Petrilli: INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon Bérard
Bénédicte F. Py: Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon

Nature Communications, 2021, vol. 12, issue 1, 1-15

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.

Date: 2021
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DOI: 10.1038/s41467-021-26142-w

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