Regulation of Nucleoporins by Interferon

描述（由申请人提供）：真核细胞的细胞核和细胞质之间的分子运动由核转运机制介导。一般而言，为了从细胞核输入或输出，分子1）与转运受体结合，2）通过存在于核膜中的核孔复合物（NPC）转运，3）并从NPC易位到核内或细胞质靶位点。这些是控制分子如转录因子、RNA、激酶和病毒颗粒进入和离开核的关键步骤。这种机制的破坏与癌症有关。NPC蛋白（核孔蛋白或NUP）与白血病中的染色体重排相关。核蛋白也是病毒蛋白的靶点。我们最近的研究结果表明，上调两个主要的Nup，Nup98和Nup96，干扰素（IFN）逆转mRNA核输出抑制介导的病毒蛋白。这些结果表明Nups在抗病毒反应和其他IFN介导的过程中的作用，如先天免疫和细胞增殖。我们的长期目标是了解核转运机制的分子机制，以及它们如何通过不同的信号通路进行调节。核心假设是Nups的一个子集受到细胞外信号的高度调节，促进分子的核输入和输出，并且也是病毒蛋白和其他致病因子的靶点。我们将努力实现以下具体目标：1.表征Nup98和Nup96介导的核转运途径的Sec 13和新组分。2.确定Secl3和Nup98和Nup96介导的途径的新成分对NPC的结构、主动和被动转运的作用。3.确定病毒蛋白质破坏Nup98和Nup96功能的分子机制及其通过IFN途径的调节。将使用高分辨率显微镜、生物化学和遗传学方法。因此，我们的研究提出了关于Nup功能和调节的创新发现，这对于推进核转运领域至关重要，对于理解Nup在白血病和IFN介导的过程中的作用也至关重要，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.