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

Xuan Li, Sarah Thome, Xiaodan Ma, Mamta Amrute-Nayak, Alison Finigan, Lauren Kitt, Leanne Masters, John R. James, Yuguang Shi, Guoyu Meng, Ziad Mallat

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27 Scopus citations

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.

Original languageEnglish (US)
Article number15986
JournalNature Communications
Volume8
DOIs
StatePublished - Jun 28 2017

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Li, X., Thome, S., Ma, X., Amrute-Nayak, M., Finigan, A., Kitt, L., Masters, L., James, J. R., Shi, Y., Meng, G., & Mallat, Z. (2017). MARK4 regulates NLRP3 positioning and inflammasome activation through a microtubule-dependent mechanism. Nature Communications, 8, [15986]. https://doi.org/10.1038/ncomms15986