MARK4 regulates NLRP3 positioning and inflammasome activation through a microtubule-dependent mechanism.
MARK4 regulates NLRP3 positioning and inflammasome activation through a microtubule-dependent mechanism.
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MARK4 通过微管依赖性机制调节 NLRP3 定位和炎症小体激活
DOI：
10.1038/ncomms15986
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发表时间：
2017-06-28
影响因子：
16.6
通讯作者：
Mallat Z
中科院分区：
文献类型：
--
作者：
Li X;Thome S;Ma X;Amrute-Nayak M;Finigan A;Kitt L;Masters L;James JR;Shi Y;Meng G;Mallat Z
NLR家族pyrin domain containing 3（NLRP 3）炎性体的过度激活涉及许多慢性炎性疾病，包括心血管疾病和阿尔茨海默病。在这里，我们发现微管亲和力调节激酶4（MARK 4）与NLRP 3结合，并将其驱动到微管组织中心，从而在单个细胞内形成一个大的炎性斑点复合物。MARK 4敲低或敲除，或MARK 4-NLRP 3相互作用的破坏，损害NLRP 3空间排列并限制炎性小体活化。我们的研究结果表明，参与调控微管动力学的进化保守蛋白如何通过控制其运输到最佳激活位点来协调NLRP 3炎性小体激活，并确定了MARK 4在先天免疫控制中的靶向功能。微管调节NLRP 3炎性体的活化，但潜在的分子机制尚不清楚。在这里，作者表明MARK 4结合NLRP 3并将其穿梭于微管组织中心以促进最佳炎性小体激活。
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. Microtubules regulate activation of the NLRP3 inflammasome, but the underlying molecular mechanism is unclear. Here the authors show that MARK4 binds NLRP3 and shuttles it to the microtubule-organizing centre to promote optimal inflammasome activation.