Cellular and Molecular Life Sciences

, Volume 74, Issue 9, pp 1755–1764 | Cite as

A novel anti-viral role for STAT3 in IFN-α signalling responses

  • Rebecca Mahony
  • Siobhán Gargan
  • Kim L. Roberts
  • Nollaig Bourke
  • Sinead E. Keating
  • Andrew G. Bowie
  • Cliona O’Farrelly
  • Nigel J. StevensonEmail author
Original Article


The cytokine, Interferon (IFN)-α, induces a wide spectrum of anti-viral mediators, via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. STAT1 and STAT2 are well characterised to upregulate IFN-stimulated gene (ISG) expression; but even though STAT3 is also activated by IFN-α, its role in anti-viral ISG induction is unclear. Several viruses, including Hepatitis C and Mumps, reduce cellular STAT3 protein levels, via the promotion of ubiquitin-mediated proteasomal degradation. This viral immune evasion mechanism suggests an undiscovered anti-viral role for STAT3 in IFN-α signalling. To investigate STAT3’s functional involvement in this Type I IFN pathway, we first analysed its effect upon the replication of two viruses, Influenza and Vaccinia. Viral plaque assays, using Wild Type (WT) and STAT3-/- Murine Embryonic Fibroblasts (MEFs), revealed that STAT3 is required for the inhibition of Influenza and Vaccinia replication. Furthermore, STAT3 shRNA knockdown also enhanced Influenza replication and hindered induction of several, well characterised, anti-viral ISGs: PKR, OAS2, MxB and ISG15; while STAT3 expression had no effect upon induction of a separate ISG group: Viperin, IFI27, CXCL10 and CCL5. These discoveries reveal, for the first time, an anti-viral role for STAT3 in the IFN-α pathway and characterise a requirement for STAT3 in the expression of specific ISGs. These findings also identify STAT3 as a therapeutic target against viral infection and highlight it as an essential pathway component for endogenous and therapeutic IFN-α responsiveness.


Janus kinase/signal transducer of activator of transcription (JAK/STAT) Interferon-alpha (IFN-α) STAT3 IFN-stimulated gene (ISG) Vaccinia virus Influenza virus Anti-viral 



Amino acid


Analysis of variance


B-cell lymphoma 6


Dendritic cell


Eukaryotic translation initiation factor 2A


Encephalomyocarditis virus


Electrophoretic mobility shift assay


Gamma-activated sequence


Hepatitis C virus


Hypoxia-inducible factor 1 alpha


Human immunodeficiency virus


Influenza A virus




Interferon alpha


IFN alpha receptor




IFN regulatory factor


IFN-Stimulated Gene


IFN-stimulated gene factor 3


IFN-stimulated response element


Janus kinase


Madin–Darby canine kidney


Murine embryonic fibroblast


Major histocompatibility complex


Matrix metalloproteinase


Myxovirus resistance gene A/B


Natural killer


2′-5′-Oligoadenylate synthetase 2


Protein kinase R


Pathogen recognition receptor


Quantitative real time polymerase chain reaction


Retinoic acid-inducible gene I


Rabbit kidney 13


Ribosomal protein S15


Src Homology 2


Short hairpin RNA


Sis-inducible element


Suppressor of cytokine signalling


Signal transducer and activator of transcription


Tumour necrosis factor alpha


Transforming growth factor beta


Tyrosine kinase 2


Vaccinia virus


Vesicular stomatitis virus


Wild type



We would like to thank Prof. Valeria Poli (University of Turin) for MEFs and Prof. Bertrand Jacobs (Arizona State University) for the Vaccinia virus. In addition, we wish to thank the Health Research Board (POR-20120-57) and Science Foundation Ireland (12/IA/1667) for funding this work.

Supplementary material

18_2016_2435_MOESM1_ESM.docx (112 kb)
Supplementary material 1 (DOCX 112 kb)


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Copyright information

© Springer International Publishing 2016

Authors and Affiliations

  1. 1.School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute (TBSI)Trinity College DublinDublinIreland
  2. 2.Department of Microbiology, Moyne Institute of Preventive Medicine, School of Genetics and MicrobiologyTrinity College DublinDublinIreland
  3. 3.School of Medicine, Trinity Biomedical Sciences Institute (TBSI)Trinity College DublinDublinIreland
  4. 4.Centre for Innate Immunity and Infectious DiseasesHudson Institute of Medical ResearchClaytonAustralia

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