Characterizing the nuclear pore complex-T cell receptor connection

项目摘要 核孔复合物（NPC）是连接细胞核和细胞质的大型多蛋白通道。在 除了在控制核质转运中的作用外，NPC在基因表达中也起着关键作用 调控NPC及其组分（核孔蛋白）调控基因表达的分子机制 在哺乳动物细胞中的表达仍然知之甚少。最近的证据表明，NPC具有重要的 在免疫系统中发挥作用。CD4+ T淋巴细胞是适应性免疫应答的核心参与者。 这些细胞协助B细胞产生抗体，帮助CD8+ T淋巴细胞清除感染， 肿瘤生长，刺激巨噬细胞活性，将免疫细胞募集到活动性感染和炎症部位， 并发挥对控制免疫应答的程度至关重要的调节作用。CD4+ T淋巴细胞 通过刺激质膜上的T细胞受体（TCR）激活。TCR参与结果 在调节T细胞活化、增殖、功能和存活的TCR信号级联的启动中。 我们最近发现，核孔复合物组分Nup210在传递中具有关键作用， TCR信号，以及CD4+ T细胞的活化和存活。我们发现Nup210调节T细胞 通过响应TCR刺激调节基因表达来激活。我们的研究结果表明， 质膜和核膜之间的协调活动是正确的 TCR信号的传递和TCR诱导基因的有效表达。在本建议中，我们的目标是 建立TCR刺激信号如何从质膜传递到NPC处的Nup210（Aim 1），剖析Nup210在TCR过程中如何调节NFAT和STAT转录因子的转录活性 Caveolin 2蛋白在Nup210调节TCR诱导的基因表达中的作用 表达式（目标3）。除了提供新的见解基因表达调控的机制， 核孔蛋白，我们希望我们的工作将导致一个新的机制的特点，调节T细胞 这些功能可以潜在地用于在基于免疫的疗法中调节T细胞活性。

PROJECT SUMMARY Nuclear pore complexes (NPCs) are large multiprotein channels that connect the nucleus with the cytoplasm. In addition to their role in controlling nucleocytoplasmic transport, NPCs play key roles in gene expression regulation. The molecular mechanisms employed by NPCs and its components (nucleoporins) to regulate gene expression in mammalian cells are still poorly understood. Recent evidence indicates that NPCs have important functions in the immune system. CD4+ T lymphocytes are central players of the adaptive immune response. These cells assist B cells with antibody production, help CD8+ T lymphocytes to clear infections and to control tumor growth, stimulate macrophage activity, recruit immune cells to sites of active infection and inflammation, and exert regulatory roles that are essential to control the extent of the immune response. CD4+ T lymphocytes activate through the stimulation of their T cell receptor (TCR) at the plasma membrane. TCR engagement results in the initiation of the TCR signaling cascade that regulates T cell activation, proliferation, function and survival. We recently identified that the nuclear pore complex component Nup210 has a critical role in the transmission of TCR signals, and in the activation and survival of CD4+ T cells. We found that Nup210 regulates T cell activation by modulating gene expression in response to TCR stimulation. Our findings suggest that a coordinated activity between the plasma membrane and the nuclear envelope is required for the proper transmission of TCR signals and the efficient expression of TCR-induced genes. In this proposal we aim to establish how the TCR stimulation signal is communicated from the plasma membrane to Nup210 at NPCs (Aim 1), to dissect how Nup210 regulates the transcriptional activity NFAT and STAT transcription factors during TCR signaling (Aim 2), and to uncover the role of the Caveolin 2 protein in Nup210-regulation of TCR-induced gene expression (Aim 3). Besides offering novel insights into the mechanisms of gene expression modulation by nucleoporins, we expect our work will result in the characterization of a new mechanism of regulation of T cell function that could potentially be exploited to modulate T cell activity in immune-based therapies.