Exportin-1-dependent nuclear export of DEAD-box helicase DDX3X is central to its role in antiviral immunity

Steven M. Heaton, Sarah C. Atkinson, Melissa N. Sweeney, Sundy N. Y. Yang, David A. Jans, Natalie A. Borg

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13 Citations (Scopus)


DEAD-box helicase 3, X-linked (DDX3X) regulates the retinoic acid-inducible gene I

(RIG-I)-like receptor (RLR)-mediated antiviral response, but can also be a host factor contributing to the replication of viruses of significance to human health, such as human immunodeficiency virus type 1 (HIV-1). These roles are mediated in part through its ability to actively shuttle between the nucleus and the cytoplasm to modulate gene expression, although the tra_cking mechanisms, and impact thereof on immune signaling and viral infection, are incompletely defined. We confirm that DDX3X nuclear export is mediated by the nuclear transporter exportin-1/CRM1, dependent on an N-terminal, leucine-rich nuclear export signal (NES) and the monomeric guanine nucleotide binding protein Ran in activated GTP-bound form. Transcriptome profiling and ELISA show that exportin-1-dependent export of DDX3X to the cytoplasm strongly impacts IFN-β production and the upregulation of immune genes in response to infection. That this is key to DDX3X’s antiviral role was indicated by enhanced infection by human parainfluenza virus-3 (hPIV-3)/elevated virus production when the DDX3X NES was inactivated. Our results highlight a link between nucleocytoplasmic distribution of DDX3X and its role in antiviral immunity, with strong relevance to hPIV-3, as well as other viruses such as HIV-1.

Original languageEnglish
Article number1181
Number of pages22
Issue number10
Publication statusPublished - Oct 2019


  • Antiviral immunity
  • CRM1
  • DDX3X
  • Exportin-1
  • NES
  • Nuclear export
  • Parainfluenza virus

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