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首页> 外文期刊>The Journal of biological chemistry >Membrane Microdomains and Cytoskeleton Organization Shape and Regulate the IL-7 Receptor Signalosome in Human CD4 T-cells
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Membrane Microdomains and Cytoskeleton Organization Shape and Regulate the IL-7 Receptor Signalosome in Human CD4 T-cells

机译：膜微瘤和细胞骨架组织形状和调节人CD4 T细胞中的IL-7受体信号组

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摘要

Interleukin (IL)-7 is the main homeostatic regulator of CD4 T-lymphocytes (helper) at both central and peripheral levels. Upon activation by IL-7, several signaling pathways, mainly JAK/STAT, PI3K/Akt and MAPK, induce the expression of genes involved in T-cell differentiation, activation, and proliferation. We have analyzed the early events of CD4 T-cell activation by IL-7. We have shown that IL-7 in the first few min induces the formation of cholesterol-enriched membrane microdomains that compartmentalize its activated receptor and initiate its anchoring to the cytoskeleton, supporting the formation of the signaling complex, the signalosome, on the IL-7 receptor cytoplasmic domains. Here we describe by stimulated emission depletion microscopy the key roles played by membrane microdomains and cytoskeleton transient organization in the IL-7-regulated JAK/STAT signaling pathway. We image phospho-STAT5 and cytoskeleton components along IL-7 activation kinetics using appropriate inhibitors. We show that lipid raft inhibitors delay and reduce IL-7-induced JAK1 and JAK3 phosphorylation. Drug-induced disassembly of the cytoskeleton inhibits phospho-STAT5 formation, transport, and translocation into the nucleus that controls the transcription of genes involved in T-cell activation and proliferation. We fit together the results of these quantitative analyses and propose the following mechanism. Activated IL-7 receptors embedded in membrane microdomains induce actin-microfilament meshwork formation, anchoring microtubules that grow radially from rafted receptors to the nuclear membrane. STAT5 phosphorylated by signalosomes are loaded on kinesins and glide along the microtubules across the cytoplasm to reach the nucleus 2 min after IL-7 stimulation. Radial microtubules disappear 15 min later, while transversal microtubules, independent of phospho-STAT5 transport, begin to bud from the microtubule organization center.
机译：白细胞介素（IL）-7是中环和外周水平的CD4 T淋巴细胞（辅助）的主要稳态调节剂。在IL-7激活后，几种信号通路，主要是JAK / STAT，PI3K / AKT和MAPK，诱导参与T细胞分化，活化和增殖的基因的表达。我们分析了IL-7的CD4 T细胞活化的早期事件。我们已经表明，IL-7在前几分钟中诱导富含胆固醇的膜微膜的形成，使其活化的受体分组并引发其锚固到细胞骨架，支持在IL-7上的信号组络合物的形成。受体细胞质结构域。在这里，我们通过刺激的排放耗尽显微镜描述了IL-7调节的JAK /统计信号通路中膜微瘤和细胞骨架瞬态组织发挥的关键角色。我们使用适当的抑制剂沿IL-7活化动力学进行磷酸-TAT5和细胞骨架组分。我们表明脂质筏抑制剂延迟并减少IL-7诱导的JAK1和JAK3磷酸化。药物诱导的细胞骨架的拆卸抑制磷酸-TAT5形成，转运和易位到控制参与T细胞活化和增殖的基因的转录中的细胞核中。我们融合了这些定量分析的结果，并提出了以下机制。嵌入膜微膜中的活化IL-7受体诱导肌动蛋白微丝网状形成，锚固微管，其从圆形受体到核膜径向生长。 STAT5由Signalosomes磷酸化被加载在Kinesins上并在IL-7刺激后沿细胞质沿细胞质沿微管滑动。径向微管后15分钟后，横向微管，独立于磷酸盐 - Stat5运输，从微管组织中心开始萌芽。

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