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NLRP3 phosphorylation in its LRR domain critically regulates inflammasome assembly

Author

Listed:
  • Tingting Niu

    (Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon
    East China Normal University)

  • 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)

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.

Suggested Citation

  • Tingting Niu & Charlotte Rosny & Séverine Chautard & Amaury Rey & Danish Patoli & Marine Groslambert & Camille Cosson & Brice Lagrange & Zhirong Zhang & Orane Visvikis & Sabine Hacot & Maggy Hologne &, 2021. "NLRP3 phosphorylation in its LRR domain critically regulates inflammasome assembly," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26142-w
    DOI: 10.1038/s41467-021-26142-w
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    References listed on IDEAS

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    1. Ryan J. Golden & Beibei Chen & Tuo Li & Juliane Braun & Hema Manjunath & Xiang Chen & Jiaxi Wu & Vanessa Schmid & Tsung-Cheng Chang & Florian Kopp & Andres Ramirez-Martinez & Vincent S. Tagliabracci &, 2017. "An Argonaute phosphorylation cycle promotes microRNA-mediated silencing," Nature, Nature, vol. 542(7640), pages 197-202, February.
    2. Brice Lagrange & Sacha Benaoudia & Pierre Wallet & Flora Magnotti & Angelina Provost & Fanny Michal & Amandine Martin & Flaviana Di Lorenzo & Bénédicte F. Py & Antonio Molinaro & Thomas Henry, 2018. "Human caspase-4 detects tetra-acylated LPS and cytosolic Francisella and functions differently from murine caspase-11," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    3. Yuan He & Melody Y. Zeng & Dahai Yang & Benny Motro & Gabriel Núñez, 2016. "NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux," Nature, Nature, vol. 530(7590), pages 354-357, February.
    4. Ela Elyada & Ariel Pribluda & Robert E. Goldstein & Yael Morgenstern & Guy Brachya & Gady Cojocaru & Irit Snir-Alkalay & Ido Burstain & Rebecca Haffner-Krausz & Steffen Jung & Zoltan Wiener & Kari Ali, 2011. "CKIα ablation highlights a critical role for p53 in invasiveness control," Nature, Nature, vol. 470(7334), pages 409-413, February.
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