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AKT Regulates NLRP3 Inflammasome Activation by Phosphorylating NLRP3 Serine 5

Wei Zhao, Chong-Shan Shi, Kathleen Harrison, Il-Young Hwang, Neel R. Nabar, Min Wang and John H. Kehrl
J Immunol October 15, 2020, 205 (8) 2255-2264; DOI: https://doi.org/10.4049/jimmunol.2000649
Wei Zhao
*Department of Prosthodontics, College of Stomatology, Xi’an Jiaotong University, Xi’an 710004, China;
†B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
‡State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, China; and
§Department of Prosthodontics, National Clinical Research Center for Oral Disease, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
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Chong-Shan Shi
†B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
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Kathleen Harrison
†B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
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Il-Young Hwang
†B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
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Neel R. Nabar
†B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
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Min Wang
‡State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, China; and
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John H. Kehrl
†B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
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Key Points

  • AKT phosphorylates NLRP3 at S5, preventing self-oligomerization and IL-1β release.

  • NLRP3 S5 phosphorylation prevents TRIM31-mediated degradation during LPS priming.

Abstract

The cytosolic pattern recognition receptor NLRP3 senses host-derived danger signals and certain microbe-derived products in both humans and rodents. NLRP3 activation assembles an inflammasome complex that contains the adapter proteins ASC and caspase-1, whose activation triggers the maturation and release of the proinflammatory cytokines IL-1β and IL-18. S5 phosphorylation of NLRP3 prevents its oligomerization and activation, whereas dephosphorylation of this residue by the phosphatase PP2A allows NLRP3 activation. However, the protein kinase that mediates NLRP3 S5 phosphorylation is unknown. In this study, we show that AKT associates with NLRP3 and phosphorylates it on S5, limiting NLRP3 oligomerization. This phosphorylation event also stabilizes NLRP3 by reducing its ubiquitination on lysine 496, which inhibits its proteasome-mediated degradation by the E3 ligase Trim31. Pharmacologic manipulation of AKT kinase activity reciprocally modulates NLRP3 inflammasome-mediated IL-1β production. Inhibition of AKT reduced IL-1β production following the i.p. injection of LPS into mice. We propose that AKT, Trim31, and PP2A together modulate NLRP3 protein levels and the tendency to oligomerize, thereby setting a tightly regulated threshold for NLRP3 activation.

Footnotes

  • This research was supported by the intramural program of Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Project AI000739-25.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    BMDM
    bone marrow–derived macrophage
    DSS
    disuccinimidyl suberate
    F
    forward
    HA
    hemagglutinin
    LRR
    leucine-rich repeat
    PH
    pleckstrin homology
    PYD
    pyrin domain
    qRT-PCR
    quantitative real-time PCR
    R
    reverse
    siRNA
    small interfering RNA
    WT
    wild-type.

  • Received June 1, 2020.
  • Accepted August 17, 2020.
  • Copyright © 2020 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 205 (8)
The Journal of Immunology
Vol. 205, Issue 8
15 Oct 2020
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AKT Regulates NLRP3 Inflammasome Activation by Phosphorylating NLRP3 Serine 5
Wei Zhao, Chong-Shan Shi, Kathleen Harrison, Il-Young Hwang, Neel R. Nabar, Min Wang, John H. Kehrl
The Journal of Immunology October 15, 2020, 205 (8) 2255-2264; DOI: 10.4049/jimmunol.2000649

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AKT Regulates NLRP3 Inflammasome Activation by Phosphorylating NLRP3 Serine 5
Wei Zhao, Chong-Shan Shi, Kathleen Harrison, Il-Young Hwang, Neel R. Nabar, Min Wang, John H. Kehrl
The Journal of Immunology October 15, 2020, 205 (8) 2255-2264; DOI: 10.4049/jimmunol.2000649
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