Inhibition of IFN-gamma-induced STAT1 tyrosine phosphorylation by human CMV is mediated by SHP2.
Human CMV (HCMV) is a ubiquitous beta-herpesvirus which has developed several mechanisms of escape from the immune system. IFN-gamma-induced signaling relies on the integrity of the JAK/STAT pathway which is regulated by phosphorylation steps and leads to nuclear translocation of tyrosine-phosphorylated STAT1 (STAT1-P-Tyr), and its binding to IFN-gamma activation site sequences of IFN-gamma-inducible promoters. Activation of those promoters leads to the expression of genes involved in the immune response and in the antiviral effects of IFN-gamma. Src homology region 2 domain-containing phosphatase 2 (SHP2) is a ubiquitous phosphatase involved in the regulation of IFN-gamma-mediated tyrosine phosphorylation. Several mechanisms account for the inhibition IFN-gamma signaling pathway by HCMV. In this study, we have identified a new mechanism that involved the inhibition of STAT1 tyrosine phosphorylation within 12-24 h postinfection. This defect was dependent on HCMV transcription. Consequences were impaired nuclear translocation of STAT1-P-Tyr, inhibition of IFN-gamma activation site-STAT1 interaction, and inhibition of HLA-DR expression. Expression of indoleamine-2,3-dioxygenase which is involved in the antiviral effects of IFN-gamma was also inhibited. Treatment of cells with sodium orthovanadate rescued STAT1 tyrosine phosphorylation, suggesting that a tyrosine phosphatase was involved in this inhibition. Coimmunoprecipitation of STAT1 and SHP2 was induced by HCMV infection, and SHP2 small interfering RNA restored the expression of STAT1-P-Tyr. Our data suggest that SHP2 activation induced by HCMV infection is responsible for the down-regulation of IFN-gamma-induced STAT1 tyrosine phosphorylation.
Baron
Michel
M
Institut National de la Santé et de la Recherche Médicale Unité 563, Centre de Physiopathologie de Toulouse Purpan, Paul Sabatier University, Toulouse, France.
Davignon
Jean-Luc
JL
D021581:Active Transport, Cell Nucleus / Q000276:immunology; D002460:Cell Line; D002467:Cell Nucleus / Q000276:immunology* / Q000378:metabolism; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000201:enzymology / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D006684:HLA-DR Antigens / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D053612:Janus Kinases / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000276:immunology* / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013997:Time Factors; D014443:Tyrosine / Q000276:immunology / Q000378:metabolism
D006684:HLA-DR Antigens; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014443:Tyrosine; D007371:Interferon-gamma; D053612:Janus Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11