Measles virus suppresses interferon-alpha signaling pathway: suppression of Jak1 phosphorylation and association of viral accessory proteins, C and V, with interferon-alpha receptor complex.
To establish infections, viruses use various strategies to suppress the host defense mechanism, such as interferon (IFN)-induced antiviral state. We found that cells infected with a wild strain of measles virus (MeV) displayed nearly complete suppression of IFN-alpha-induced antiviral state, but not IFN-gamma-induced state. This phenomenon is due to the suppression of IFN-alpha-inducible gene expression at a transcriptional level. In the IFN-alpha signal transduction pathway, Jak1 phosphorylation induced by IFN-alpha is dramatically suppressed in MeV-infected cells; however, phosphorylation induced by IFN-gamma is not. We performed immunoprecipitation experiments using antibodies against type 1 IFN receptor chain 1 (INFAR1) and antibody against RACK1, which is reported to be a scaffold protein interacting with type I IFN receptor chain 2 and STAT1. These experiments indicated that IFNAR1 forms a complex containing the MeV-accessory proteins C and V, RACK1, and STAT1 in MeV-infected cells but not in uninfected cells. Composition of this complex in the infected cells altered little by IFN-alpha treatment. These results indicate that MeV suppresses the IFN-alpha, but not IFN-gamma, signaling pathway by inhibition of Jak1 phosphorylation. Our data suggest that functional disorder of the type I IFN receptor complex is due to "freezing" of the receptor through its association with the C and/or V proteins of MeV.
Yokota
Shin-ichi
S
Department of Microbiology, Sapporo Medical University School of Medicine, Chuo-ku, 060-8556, Sapporo, Japan.
Saito
Hiroyuki
H
Kubota
Toru
T
Yokosawa
Noriko
N
Amano
Ken-ichi
K
Fujii
Nobuhiro
N
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha / Q000378:metabolism*; D053613:Janus Kinase 1; D008459:Measles virus / Q000378:metabolism / Q000472:pathogenicity*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism*
D004268:DNA-Binding Proteins; C494227:IRF9 protein, human; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; D010750:Phosphoproteins; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; C069181:V protein, measles virus; D014764:Viral Proteins; D053633:Receptor, Interferon alpha-beta; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1