Journal
INNATE IMMUNITY
Volume 19, Issue 5, Pages 516-530Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1177/1753425912473345
Keywords
Viral infection; innate immunity; type III interferon; interferon regulatory factor; kinase signalling
Categories
Funding
- Medical Research Council of the Academy of Finland [252252, 256159]
- Sigrid Juselius Foundation
- Academy of Finland (AKA) [252252, 252252] Funding Source: Academy of Finland (AKA)
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Activation of host innate antiviral responses are mediated by retinoic-acid inducible gene I (RIG-I)-like receptors, RIG-I and melanoma differentiation-associated gene 5, and TLRs 3, 7, 8 and 9, recognising different types of viral nucleic acids. The major components of the RIG-I- and TLR pathways have putatively been identified, but previously unrecognised kinases may contribute to virus infection-induced activation of the IFN response. Here, we screened a human kinase cDNA library, termed the kinome, using an IFN-1 promoter-driven luciferase reporter assay in HEK293 cells during Sendai virus infection. Of the 568 kinases analysed, nearly 50 enhanced IFN-1 gene expression at least twofold in response to Sendai virus infection. The best activators were FYN (FYN oncogene related to SRC, FGR, YES), serine/threonine kinase 24, activin A receptor type 1 and SRPK1 (SFRS protein kinase 1). These kinases enhanced RIG-I-dependent IFN-1 promoter activation via IFN-stimulated response and NF-B elements, as confirmed using mutant IFN-1 promoter constructs. FYN and SRPK1 enhanced IFN-1 and CXCL10 protein production via the RIG-I pathway, and stimulated RIG-I and MyD88-dependent phosphorylation of IRF3 and IRF7 transcription factors, respectively. We conclude that several previously unrecognised kinases, particularly FYN and SRPK1, positively regulate IFN-1 and similarly regulated cytokine and chemokine genes during viral infection.
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