title: Human kinome analysis reveals novel kinases contributing to virus infection and retinoic-acid inducible gene I-induced type I and type III IFN gene expression.
abstract: 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-λ1 promoter-driven luciferase reporter assay in HEK293 cells during Sendai virus infection. Of the 568 kinases analysed, nearly 50 enhanced IFN-λ1 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-λ1 promoter activation via IFN-stimulated response and NF-κB elements, as confirmed using mutant IFN-λ1 promoter constructs. FYN and SRPK1 enhanced IFN-λ1 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-λ1 and similarly regulated cytokine and chemokine genes during viral infection.
authors: 1Department of Infectious Disease Surveillance and Control, National Institute for Health and Welfare (THL), Helsinki, Finland.
authors: Laura
authors: L
authors: Nousiainen
authors: Maarit
authors: M
authors: Sillanpää
authors: Miao
authors: M
authors: Jiang
authors: James
authors: J
authors: Thompson
authors: Jussi
authors: J
authors: Taipale
authors: Ilkka
authors: I
authors: Julkunen
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D015723:Gene Library; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D000072640:Interferon-Induced Helicase, IFIH1; D007372:Interferons; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D011971:Receptors, Immunologic; D010253:Respirovirus Infections / Q000276:immunology / Q000378:metabolism*; D029082:Sendai virus / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics; D051193:Toll-Like Receptors / Q000378:metabolism; D015854:Up-Regulation; D000095022:Interferon Lambda
chemical_list: D030201:Activin Receptors, Type I; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D007372:Interferons; D007378:Interleukins; D017346:Protein Serine-Threonine Kinases; D051076:Proto-Oncogene Proteins c-fyn; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C087728:SRPK1 protein, human; C425423:ACVR1 protein, human; C452820:RIGI protein, human; C452815:IFIH1 protein, human
keywords: Viral infection; innate immunity; interferon regulatory factor; kinase signalling; type III interferon