Dong Baoxia, Zhang Steven S, Gao Wen, Su Haichun, Chen Jun, Jin Fuzi, Bhargava Ajay, Chen Xiequn, Jorgensen Lars, Alberts Arthur S, Zhang Jinyi, Siminovitch Katherine A
Departments of Immunology and Molecular Genetics, University of Toronto, Mount Sinai Hospital, Samuel Lunenfeld Research Institute and Toronto General Research Institutes, Toronto, Ontario, Canada ; Department of Hematology, Xijing Hospital, Xian, Shaanxi, China.
PLoS One. 2013 Nov 18;8(11):e80500. doi: 10.1371/journal.pone.0080500. eCollection 2013.
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) 3β as well as hyperphosphorylation and reduced levels of APC in migrating T cells. These findings identify essential roles for the mDia1 formin in modulating GSK3β-dependent MT contributions to induction of T-cell polarity, adhesion and motility.
哺乳动物的Diaphanous相关成肌蛋白（mDia1）是一种受Rho调节的细胞骨架调节剂，已被证明可促进T淋巴细胞趋化作用以及与抗原呈递细胞的相互作用，但mDia1在这些过程中发挥作用的机制尚未明确。在此我们表明，mDia1基因敲除的T细胞表现出淋巴细胞功能相关抗原1（LFA-1）介导的T细胞黏附、迁移及体内运输受损。这些缺陷与微管（MT）极化和稳定性受损、MT动力学改变以及LFA-1激活后迁移T细胞中MT正端蛋白腺瘤性息肉病大肠杆菌（APC）的外周聚集减少有关。mDia1的缺失还导致迁移T细胞中糖原合酶激酶（GSK）3β的诱导性失活受损，以及APC的过度磷酸化和水平降低。这些发现确定了mDia1成肌蛋白在调节GSK3β依赖的MT对T细胞极性、黏附和运动诱导的作用中的重要作用。
