Inhibition of RAN attenuates influenza a virus replication and nucleoprotein nuclear export.

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  • Additional Information
    • Source:
      Publisher: Taylor & Francis Country of Publication: United States NLM ID: 101594885 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2222-1751 (Electronic) Linking ISSN: 22221751 NLM ISO Abbreviation: Emerg Microbes Infect Subsets: MEDLINE
    • Publication Information:
      Publication: 2019- : [Philadelphia, PA] : Taylor & Francis
      Original Publication: New York : NPG, 2012-2018.
    • Subject Terms:
      Virus Replication*/drug effects ; ran GTP-Binding Protein*/metabolism ; ran GTP-Binding Protein*/genetics ; Antiviral Agents*/pharmacology ; Influenza A virus*/drug effects ; Influenza A virus*/physiology ; Active Transport, Cell Nucleus* ; Exportin 1 Protein* ; Karyopherins*/metabolism ; Karyopherins*/antagonists & inhibitors; Humans ; Animals ; Dogs ; Receptors, Cytoplasmic and Nuclear/metabolism ; Receptors, Cytoplasmic and Nuclear/genetics ; Madin Darby Canine Kidney Cells ; Viral Nonstructural Proteins/metabolism ; Viral Nonstructural Proteins/genetics ; Mice ; Piperidines/pharmacology ; Influenza, Human/virology ; A549 Cells ; Nucleoproteins/metabolism ; Nucleoproteins/genetics ; HEK293 Cells ; Cell Line ; Cell Nucleus/metabolism ; Ribonucleoproteins/metabolism ; Ribonucleoproteins/genetics
    • Abstract:
      Nuclear export of the viral ribonucleoprotein (vRNP) is a critical step in the influenza A virus (IAV) life cycle and may be an effective target for the development of anti-IAV drugs. The host factor ras-related nuclear protein (RAN) is known to participate in the life cycle of several viruses, but its role in influenza virus replication remains unknown. In the present study, we aimed to determine the function of RAN in influenza virus replication using different cell lines and subtype strains. We found that RAN is essential for the nuclear export of vRNP, as it enhances the binding affinity of XPO1 toward the viral nuclear export protein NS2. Depletion of RAN constrained the vRNP complex in the nucleus and attenuated the replication of various subtypes of influenza virus. Using in silico compound screening, we identified that bepotastine could dissociate the RAN-XPO1-vRNP trimeric complex and exhibit potent antiviral activity against influenza virus both in vitro and in vivo . This study demonstrates the important role of RAN in IAV replication and suggests its potential use as an antiviral target.
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    • Contributed Indexing:
      Keywords: Influenza A virus; RAN; bepotastine; nuclear export; viral ribonucleoprotein
    • Accession Number:
      EC 3.6.5.2 (ran GTP-Binding Protein)
      0 (Antiviral Agents)
      0 (Exportin 1 Protein)
      0 (Karyopherins)
      0 (Receptors, Cytoplasmic and Nuclear)
      0 (RAN protein, human)
      0 (Viral Nonstructural Proteins)
      0 (Piperidines)
      0 (NS2 protein, influenza virus A)
      0 (Nucleoproteins)
      0 (Ribonucleoproteins)
    • Publication Date:
      Date Created: 20240801 Date Completed: 20240812 Latest Revision: 20240923
    • Publication Date:
      20240923
    • Accession Number:
      PMC11321118
    • Accession Number:
      10.1080/22221751.2024.2387910
    • Accession Number:
      39087696