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SUMO-mediated regulation of NLRP3 modulates inflammasome activity

Author

Listed:
  • Rachael Barry

    (Chester Beatty Laboratories
    Imperial College London)

  • Sidonie Wicky John

    (Chester Beatty Laboratories)

  • Gianmaria Liccardi

    (Chester Beatty Laboratories)

  • Tencho Tenev

    (Chester Beatty Laboratories)

  • Isabel Jaco

    (Chester Beatty Laboratories)

  • Chih-Hong Chen

    (Beckman Research Institute of City of Hope, Duarte)

  • Justin Choi

    (Beckman Research Institute of City of Hope, Duarte)

  • Paulina Kasperkiewicz

    (Wroclaw University of Technology)

  • Teresa Fernandes-Alnemri

    (Thomas Jefferson University)

  • Emad Alnemri

    (Thomas Jefferson University)

  • Marcin Drag

    (Wroclaw University of Technology)

  • Yuan Chen

    (Beckman Research Institute of City of Hope, Duarte)

  • Pascal Meier

    (Chester Beatty Laboratories)

Abstract

The NLRP3 inflammasome responds to infection and tissue damage, and rapidly escalates the intensity of inflammation by activating interleukin (IL)-1β, IL-18 and cell death by pyroptosis. How the NLRP3 inflammasome is negatively regulated is poorly understood. Here we show that NLRP3 inflammasome activation is suppressed by sumoylation. NLRP3 is sumoylated by the SUMO E3-ligase MAPL, and stimulation-dependent NLRP3 desumoylation by the SUMO-specific proteases SENP6 and SENP7 promotes NLRP3 activation. Defective NLRP3 sumoylation, either by NLRP3 mutation of SUMO acceptor lysines or depletion of MAPL, results in enhanced caspase-1 activation and IL-1β release. Conversely, depletion of SENP7 suppresses NLRP3-dependent ASC oligomerisation, caspase-1 activation and IL-1β release. These data indicate that sumoylation of NLRP3 restrains inflammasome activation, and identify SUMO proteases as potential drug targets for the treatment of inflammatory diseases.

Suggested Citation

  • Rachael Barry & Sidonie Wicky John & Gianmaria Liccardi & Tencho Tenev & Isabel Jaco & Chih-Hong Chen & Justin Choi & Paulina Kasperkiewicz & Teresa Fernandes-Alnemri & Emad Alnemri & Marcin Drag & Yu, 2018. "SUMO-mediated regulation of NLRP3 modulates inflammasome activity," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05321-2
    DOI: 10.1038/s41467-018-05321-2
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