Involvement of LIM kinase 1 in actin polarization in human CD4 T cells.
Involvement of LIM kinase 1 in actin polarization in human CD4 T cells.
复制标题
DOI：
10.4161/cib.20165
复制
发表时间：
2012-07-01
影响因子：
--
通讯作者：
Wu Y
中科院分区：
文献类型：
--
作者：
Xu X;Guo J;Vorster P;Wu Y
趋化因子与同源受体结合诱导肌动蛋白动力学，是T细胞迁移和趋化运动的主要驱动力。HIV-1与趋化因子辅助受体CXCR4结合后启动趋化信号，模拟趋化因子诱导的肌动蛋白动力学，促进感染过程，如进入、早期DNA合成和核迁移。最近，我们发现HIV引发的早期肌动蛋白聚合是通过rac1-PAK1/2-LIMK1-cofilin途径介导的。通过shRNA敲除抑制LIMK1(LIM结构域激酶1)，一种磷酸化Cofilin的激酶，减少了肌动蛋白聚合和T细胞对SDF-1的趋化。LIMK1基因敲除的T细胞也支持较低的病毒进入、DNA合成和核迁移，这表明LIMK1介导的肌动蛋白动力学在HIV-1感染的启动过程中发挥了关键作用。令人惊讶的是，在CEM-SS T细胞中，LIMK1基因敲除并没有导致磷酸化胶丝蛋白与总胶丝蛋白比率的整体变化，尽管细胞中肌动蛋白细丝的数量明显减少。LIMK1基因敲除细胞中丝状肌动蛋白的减少主要发生在富含F-肌动蛋白的极化帽区。这些结果提示，LIMK1可能参与了转化T细胞的自发肌动蛋白极化。LIMK1基因敲除对T细胞趋化性的抑制可能是由于抑制了LIMK1的局部激活和cofilin磷酸化，这是极化肌动蛋白聚合实现细胞定向迁移所必需的。LIMK1基因敲除对HIV-1感染的抑制也可能是由于富含肌动蛋白的膜突起减少，这可能是T细胞首选的病毒进入部位。
Chemokine binding to cognate receptors induces actin dynamics that are a major driving force for T cell migration and chemotactic motility. HIV-1 binding to the chemokine coreceptor CXCR4 initiates chemotactic signaling, mimicking chemokine-induced actin dynamics to facilitate infection processes such as entry, early DNA synthesis, and nuclear migration. Recently, we identified that HIV-triggered early actin polymerization is mediated through the Rac1-PAK1/2-LIMK1-cofilin pathway. Inhibition of LIMK1 (LIM domain kinase 1), a kinase phosphorylating cofilin, through shRNA knockdown decreases actin polymerization and T cell chemotaxis toward SDF-1. The LIMK1 knockdown T cells also supported lower viral entry, DNA synthesis and nuclear migration, suggesting a critical role of LIMK1-mediated actin dynamics in the initiation of HIV-1 infection. Surprisingly, LIMK1 knockdown in CEM-SS T cells did not lead to an overall change in the ratio of phospho-cofilin to total cofilin although there was a measurable decrease in the amount of actin filaments in cells. The decrease in filamentous actin in LIMK1 knockdown cells was found to mainly occur in polarized cap region rich in F-actin. These results suggest that LIMK1 may be involved in spontaneous actin polarization in transformed T cells. The inhibition of T cell chemotaxis by LIMK1 knockdown likely result from inhibition of localized LIMK1 activation and cofilin phosphorylation that are required for polarized actin polymerization for directional cell migration. The inhibition of HIV-1 infection by LIMK1 knockdown may also result from the decrease of actin-rich membrane protrusions that may be preferred viral entry sites in T cells.