Regulation of Nucleoporins by Interferon

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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.