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

doi:10.1038/ncomms15986

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

Research output: Contribution to journal › Article › peer-review

118 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 language	English (US)
Article number	15986
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15986
State	Published - Jun 28 2017

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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title = "MARK4 regulates NLRP3 positioning and inflammasome activation through a microtubule-dependent mechanism",

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.",

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T1 - MARK4 regulates NLRP3 positioning and inflammasome activation through a microtubule-dependent mechanism

AU - Li, Xuan

AU - Thome, Sarah

AU - Ma, Xiaodan

AU - Amrute-Nayak, Mamta

AU - Finigan, Alison

AU - Kitt, Lauren

AU - Masters, Leanne

AU - James, John R.

AU - Shi, Yuguang

AU - Meng, Guoyu

AU - Mallat, Ziad

PY - 2017/6/28

Y1 - 2017/6/28

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AB - 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.

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

Abstract

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