A role for the nuclear transport machinery in supporting positive-strand RNA virus infection and in regulating innate immune responses

  • Author / Creator
    Neufeldt, Christopher J
  • In eukaryotic cells, the genetic material is encapsulated in a double lipid membrane layer to form the nuclear compartment. This double membrane layer, termed the nuclear envelope, is fenestrated by pores, which are occupied by proteinaceous gateway structures termed nuclear pore complexes (NPCs). NPCs facilitate all traffic between the nucleus and cytoplasm effectively creating a selective barrier between these two compartments. Its key location at the interface between the nucleus and cytoplasm allows the NPC or it constituent proteins, termed nucleoporins or Nups, to regulate a large number of cellular pathways. This also makes the NPC an important target for many viral infections. Similar to the formation of organelles in eukaryotic cells, positive-strand RNA viruses, including hepatitis C virus, induce the formation of membrane bound replication and assembly compartments in the cytoplasm of infected cells. These membrane compartments function to both increase the efficiency of viral processes and to protect viral components from degradation or immune surveillance. The work presented here demonstrates a novel function for the NPC in cytoplasmic viral replication centers. Specifically, we show that Hepatitis C virus infection induces the relocalization of Nups to cytoplasmic regions enriched for viral proteins, which represent the viral replication complex (termed the membranous web). Our data also shows that components of the nuclear transport machinery support HCV replication and that nucleocytoplasmic transport is active at the membranous web. Moreover, our results indicate that NPCs residing in the membranous web are involved in a viral immune evasion strategy by facilitating the formation of a replication compartments that are protected from cellular immune receptors in the surrounding cytoplasm. Lastly, we present data the indicates one specific Nup, Nup358, is involved in generally regulating immune responses and is an important host factor that supports HCV infection. From these data we propose that HCV utilizes the immune regulatory function of Nup358 to inhibit host cell immune activation and facilitate viral infection. These results demonstrate that the nuclear transport machinery pays a critical role in the life cycle of positive strand RNA virus infections and indicate that the NPC has an important function in regulating host cell immune responses.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Department of Cell Biology
  • Supervisor / co-supervisor and their department(s)
    • Richard W Wozniak (Cell Biology)
  • Examining committee members and their departments
    • Michel Desjardins (University of Montreal, Pathology and Cell Biology)
    • D. Lorne Tyrrell (Medical Microbiology and Immunology)
    • Tom Hobman (Cell Biology)
    • Richard W Wozniak (Cell Biology)
    • Richard Lehner (Pediatrics)