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Inhibition of IFN--Induced STAT1 Tyrosine Phosphorylation by Human CMV Is Mediated by SHP2¹

Institut National de la Santé et de la Recherche Médicale Unité 563, Centre de Physiopathologie de Toulouse Purpan, Paul Sabatier University, Toulouse, France

Human CMV (HCMV) is a ubiquitous β-herpesvirus which has developed several mechanisms of escape from the immune system. IFN--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- activation site sequences of IFN--inducible promoters. Activation of those promoters leads to the expression of genes involved in the immune response and in the antiviral effects of IFN-. Src homology region 2 domain-containing phosphatase 2 (SHP2) is a ubiquitous phosphatase involved in the regulation of IFN--mediated tyrosine phosphorylation. Several mechanisms account for the inhibition IFN- 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- 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- 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--induced STAT1 tyrosine phosphorylation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work has been supported by Association pour la Recherche sur le Cancer and Sidaction.

² Address correspondence and reprint requests to Dr. Jean-Luc Davignon, JE 2510, Centre de Physiopathologie de Toulouse Purpan, Bâtiment C, Centre Hospitalier de l’Université Purpan, 31024 Toulouse, France. E-mail address: jean-luc.davignon{at}inserm.fr

³ Abbreviations used in this paper: HCMV, human CMV; MHC I, MHC class I; MHC II, MHC class II; IDO, indoleamine 2,3-dioxygenase; siRNA, small interfering RNA; DC, dendritic cell; SOCS, suppressors of cytokine signaling; SHP1, Src homology region 2 domain-containing phosphatase 1; SHP2, Src homology region 2 domain-containing phosphatase 2; GAS, IFN- activation site; STAT1-P-Tyr, tyrosine-phosphorylated STAT1; p.i., postinfection; EGF, epidermal growth factor.