Mammalian Diaphanous-Related Formin 1 Regulates GSK3β-Dependent Microtubule Dynamics Required for T Cell Migratory Polarization
Mammalian Diaphanous-Related Formin 1 Regulates GSK3β-Dependent Microtubule Dynamics Required for T Cell Migratory Polarization
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DOI：
10.1371/journal.pone.0080500
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发表时间：
2013-11-18
期刊：
影响因子：
3.7
通讯作者：
Siminovitch, Katherine A.
中科院分区：
文献类型：
--
作者：
Dong, Baoxia;Zhang, Steven S.;Siminovitch, Katherine A.
哺乳动物透明相关蛋白（mDia 1）是一种Rho调节的细胞骨架调节剂，可促进T淋巴细胞的趋化性和与抗原呈递细胞的相互作用，但mDia 1在这些过程中的作用机制尚不清楚。在这里，我们表明，mDia 1（-/-）T细胞表现出受损的淋巴细胞功能相关抗原1（LFA-1）介导的T细胞粘附，迁移和体内运输。这些缺陷与LFA-1接合后迁移T细胞中微管（MT）极化和稳定性受损、MT动力学改变以及MT加末端蛋白、结肠腺瘤性息肉病（APC）外周聚集减少有关。mDia 1的缺失还导致糖原合成酶激酶（GSK）3 β的诱导性失活受损以及迁移性T细胞中APC的过度磷酸化和水平降低。这些发现确定了mDia 1 β在调节GSK 3 β依赖性MT对诱导T细胞极性、粘附和运动性的贡献中的重要作用。
The mammalian diaphanous-related formin (mDia1), a Rho-regulated cytoskeletal modulator, has been shown to promote T lymphocyte chemotaxis and interaction with antigen presenting cells, but the mechanisms underpinning mDia1 roles in these processes have not been defined. Here we show that mDia1(-/-) T cells exhibit impaired lymphocyte function-associated antigen 1 (LFA-1)-mediated T cell adhesion, migration and in vivo trafficking. These defects are associated with impaired microtubule (MT) polarization and stabilization, altered MT dynamics and reduced peripheral clustering of the MT plus-end-protein, adenomatous polyposis coli (APC) in migrating T cells following LFA-1-engagement. Loss of mDia1 also leads to impaired inducible inactivation of the glycogen synthase kinase (GSK) 3 beta as well as hyperphosphorylation and reduced levels of APC in migrating T cells. These findings identify essential roles for the mDia1 formin in modulating GSK3 beta-dependent MT contributions to induction of T-cell polarity, adhesion and motility.