A Kaposi's sarcoma-associated herpesvirus protein that forms inhibitory complexes with type I interferon receptor subunits, Jak and STAT proteins, and blocks interferon-mediated signal transduction.
Type I interferons (IFNs) are important mediators of innate antiviral defense and function by activating a signaling pathway through their cognate type I receptor (IFNAR). Here we report that lytic replication of Kaposi's sarcoma-associated herpesvirus (KSHV) efficiently blocks type I IFN signaling and that an important effector of this blockade is the viral protein RIF, the product of open reading frame 10. RIF blocks IFN signaling by formation of inhibitory complexes that contain IFNAR subunits, the Janus kinases Jak1 and Tyk2, and the STAT2 transcription factor. Activation of both Tyk2 and Jak1 is inhibited, and abnormal recruitment of STAT2 to IFNAR1 occurs despite the decrement in Tyk2 activity. As a result of these actions, phosphorylation of both STAT2 and STAT1 is impaired, with subsequent failure of ISGF3 accumulation in the nucleus. The presence in the viral genome of potent inhibitors of type I IFN signaling, along with several viral genes that block IFN induction, highlights the importance of the IFN pathway in the control of this human tumor virus infection.
Bisson
Sabine A
SA
Howard Hughes Medical Institute and GW Hooper Foundation, Department of Microbiology, University of California, San Francisco, CA 94143, USA.
Page
Anne-Laure
AL
Ganem
Don
D
D001483:Base Sequence; D006367:HeLa Cells; D006566:Herpesviridae Infections / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000378:metabolism; D053613:Janus Kinase 1 / Q000378:metabolism*; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D010766:Phosphorylation; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D013379:Substrate Specificity; D053634:TYK2 Kinase / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism*; D014779:Virus Replication
C507964:IFNAR1 protein, human; C494227:IRF9 protein, human; D007370:Interferon Type I; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D014764:Viral Proteins; D053633:Receptor, Interferon alpha-beta; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D053634:TYK2 Kinase; C070139:TYK2 protein, human