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Open AccessArticle

Exportin-1-Dependent Nuclear Export of DEAD-box Helicase DDX3X is Central to its Role in Antiviral Immunity

1
Infection & Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia
2
Nuclear Signaling Laboratory, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia
*
Author to whom correspondence should be addressed.
Current address: School of Health and Biomedical Sciences, College of Science, Engineering and Health, RMIT University, Melbourne, VIC 3001, Australia.
Cells 2019, 8(10), 1181; https://doi.org/10.3390/cells8101181
Received: 15 August 2019 / Revised: 16 September 2019 / Accepted: 28 September 2019 / Published: 30 September 2019
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 trafficking 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. View Full-Text
Keywords: DDX3X; nuclear export; exportin-1; CRM1; NES; antiviral immunity; parainfluenza virus DDX3X; nuclear export; exportin-1; CRM1; NES; antiviral immunity; parainfluenza virus
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Heaton, S.M.; Atkinson, S.C.; Sweeney, M.N.; Yang, S.N.Y.; Jans, D.A.; Borg, N.A. Exportin-1-Dependent Nuclear Export of DEAD-box Helicase DDX3X is Central to its Role in Antiviral Immunity. Cells 2019, 8, 1181.

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