Regulation of Nucleoporins by Interferon

描述(申请人提供)：真核细胞的核和细胞质之间的分子运动是由核运输机械调节的。一般来说，要从细胞核输入或输出，分子1)与运输受体结合，2)通过存在于核膜中的核孔复合体运输，3)从核孔复合体转移到核内或细胞质靶点。这些都是控制转录因子、RNA、激酶和病毒颗粒等分子的核进出的关键步骤。这种机制的破坏与癌症有关。鼻咽癌蛋白(核孔蛋白或NUP)与白血病的染色体重排有关。核蛋白也是病毒蛋白的目标。我们最近的发现表明，干扰素上调两个主要核蛋白Nup98和Nup96的表达，可以逆转病毒蛋白介导的mRNA核输出抑制。这些结果表明，NUPS在抗病毒反应和其他干扰素介导的过程中发挥作用，如先天免疫和细胞增殖。我们的长期目标是了解核运输机制的分子机制以及它们是如何由不同的信号通路调节的。核心假设是，NUP的一部分高度受细胞外信号调控，促进分子的核进出口，也是病毒蛋白和其他致病因子的靶标。我们将追求以下具体目标：1.研究Nup98和Nup96介导的核运输途径(S)的第13节和新的组成成分。2.确定Secl3及其Nup98和Nup96途径的新成分(S)在鼻咽癌结构、主动和被动转运中的作用。3.确定病毒蛋白干扰Nup98和Nup96功能的分子机制及其受干扰素途径的调节。将使用高分辨率显微镜、生化和遗传学方法。因此，我们的研究在NUP的功能和调控方面提出了创新性的发现，这对推进核运输领域至关重要，也对于理解NUP在白血病和干扰素介导的过程中的作用至关重要，如抗病毒反应、先天免疫和细胞增殖。

DESCRIPTION (provided by applicant): The movement of molecules between the nucleus and the cytoplasm of eukaryotic cells is mediated by, the nuclear transport machinery. In general, to be imported or exported from the nucleus, molecules 1) bind to transport receptors, 2) are transported through nuclear pore complexes (NPCs) present in the nuclear envelope, 3) and translocate from the NPCs to intranuclear or cytoplasmic target sites. These are crucial steps for controlling nuclear entry and exit of molecules such as transcription factors, RNAs, kinases and viral particles. Disruption of this machinery has been involved in cancer. NPC proteins (nucleoporins or Nups) are associated with chromosomal rearrangements in leukemia. Nups are also targets of viral proteins. Our recent findings show that up-regulation of two major Nups, Nup98 and Nup96, by interferon (IFN) reverts mRNA nuclear export inhibition mediated by a viral protein. These results indicate a role for Nups in antiviral response and in other IFN-mediates processes such as innate immunity and cell proliferation. Our long-range goal is to understand the molecular mechanisms of the nuclear transport machinery and how they are, regulated by different signaling pathways. The central hypothesis is that a subset of Nups are highly regulated by extracellular signals, facilitate nuclear import and export of molecules, and are also target of viral proteins and other pathogenic factors. We will pursue the following specific aims: 1. To characterize Sec 13 and novel constituents of the Nup98 and Nup96-mediated nuclear transport pathway(s). 2. To determine the role of Secl3 and novel constituents of the Nup98 and Nup96-mediated pathway(s) on the structure, active and passive transport at the NPC. 3. Determine the molecular mechanisms involved in the disruption of Nup98 and Nup96 function by a viral protein and their regulation by the IFN pathway. High-resolution microscopies, biochemical and genetic approaches will be used. Thus, our research proposes innovative findings on Nup function and regulation, which are crucial to advance the nuclear transport field and are also essential for understanding the role of Nups in leukemia and IFN-mediated processes, such as antiviral response, innate immunity and cell proliferation.