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MARK4 regulates NLRP3 positioning and inflammasome activation through a microtubule-dependent mechanism

Author

Listed:
  • Xuan Li

    (University of Cambridge)

  • Sarah Thome

    (University of Cambridge)

  • Xiaodan Ma

    (State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital affiliated to Shanghai JiaoTong University School of Medicine)

  • Mamta Amrute-Nayak

    (Hannover Medical School)

  • Alison Finigan

    (University of Cambridge)

  • Lauren Kitt

    (University of Cambridge)

  • Leanne Masters

    (University of Cambridge)

  • John R. James

    (Molecular Immunity Unit, University of Cambridge, MRC-LMB)

  • Yuguang Shi

    (Barshop Institute for longevity and Aging Studies, University of Texas Health Science Center at San Antonio. Texas Research Park Campus MC 7755)

  • Guoyu Meng

    (State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital affiliated to Shanghai JiaoTong University School of Medicine)

  • Ziad Mallat

    (University of Cambridge
    Institut National de la Santé et de la Recherche Médicale)

Abstract

Excessive activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome is involved in many chronic inflammatory diseases, including cardiovascular and Alzheimer’s disease. Here we show that microtubule-affinity regulating kinase 4 (MARK4) binds to NLRP3 and drives it to the microtubule-organizing centre, enabling the formation of one large inflammasome speck complex within a single cell. MARK4 knockdown or knockout, or disruption of MARK4-NLRP3 interaction, impairs NLRP3 spatial arrangement and limits inflammasome activation. Our results demonstrate how an evolutionarily conserved protein involved in the regulation of microtubule dynamics orchestrates NLRP3 inflammasome activation by controlling its transport to optimal activation sites, and identify a targetable function for MARK4 in the control of innate immunity.

Suggested Citation

  • Xuan Li & Sarah Thome & Xiaodan Ma & Mamta Amrute-Nayak & Alison Finigan & Lauren Kitt & Leanne Masters & John R. James & Yuguang Shi & Guoyu Meng & Ziad Mallat, 2017. "MARK4 regulates NLRP3 positioning and inflammasome activation through a microtubule-dependent mechanism," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15986
    DOI: 10.1038/ncomms15986
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    Cited by:

    1. Yangci Liu & Haoming Zhai & Helen Alemayehu & Jérôme Boulanger & Lee J. Hopkins & Alicia C. Borgeaud & Christina Heroven & Jonathan D. Howe & Kendra E. Leigh & Clare E. Bryant & Yorgo Modis, 2023. "Cryo-electron tomography of NLRP3-activated ASC complexes reveals organelle co-localization," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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