Glycerol monolaurate induces filopodia formation by disrupting the association between LAT and SLP-76 microclusters
Glycerol monolaurate induces filopodia formation by disrupting the association between LAT and SLP-76 microclusters
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DOI：
10.1126/scisignal.aam9095
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发表时间：
2018-05-01
影响因子：
7.3
通讯作者：
Houtman, Jon C. D.
中科院分区：
文献类型：
--
作者：
Zhang, Michael S.;Tran, Phuong M.;Houtman, Jon C. D.
甘油单月桂酸酯（GML）是一种具有强效抗菌特性的单酸甘油酯，可抑制T细胞受体（TCR）诱导的信号传导和T细胞效应器功能。肌动蛋白重排是T细胞与抗原呈递细胞相互作用和迁移到感染部位所必需的。由于肌动蛋白重排在T细胞效应子功能中起关键作用，我们分析了GML对TCR活化后肌动蛋白细胞骨架重排的影响。我们发现，GML处理的人T细胞比未处理的T细胞粘附性差，没有形成肌动蛋白环结构，而是发展了许多不适当的肌动蛋白介导的丝状伪足。这些丝状伪足的形成不是由于破坏了肌动蛋白或微管聚合的TCR近端调节器。相反，全内反射荧光显微镜显示错误定位的肌动蛋白成核蛋白Arp 2微簇，但不是那些含有衔接蛋白SLP-76和WASp，或肌动蛋白成核蛋白ARPC 3，这是必要的TCR诱导的肌动蛋白重排。此外，SLP-76微簇与WASp和WAVE微簇共定位，但不与LAT共定位。总之，我们的数据表明，GML改变肌动蛋白细胞骨架重排，并确定GML作为T细胞抑制剂的多种功能。
Glycerol monolaurate (GML) is a monoglyceride with potent antimicrobial properties that suppresses T cell receptor (TCR)-induced signaling and T cell effector function. Actin rearrangement is needed for the interaction of T cells with antigen-presenting cells and for migration to sites of infection. Because of the critical role actin rearrangement plays in T cell effector function, we analyzed the effect of GML on the rearrangement of the actin cytoskeleton after TCR activation. We found that GML-treated human T cells were less adherent than untreated T cells and did not form actin ring structures but instead developed numerous inappropriate actin-mediated filopodia. The formation of these filopodia was not due to disruption of TCR-proximal regulators of actin or microtubule polymerization. Instead, total internal reflection fluorescence microscopy demonstrated mislocalization of actin nucleation protein Arp2 microclusters, but not those containing the adaptor proteins SLP-76 and WASp, or the actin nucleation protein ARPC3, which are necessary for TCR-induced actin rearrangement. Additionally, SLP-76 microclusters colocalized with WASp and WAVE microclusters but not with LAT. Together, our data suggest that GML alters actin cytoskeletal rearrangements and identify diverse functions for GML as a T cell-suppressive agent.