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Journal of Virology, May 2009, p. 5056-5066, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.02516-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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{triangledown}

Sabine A. Bisson,{dagger} Anne-Laure Page,{dagger} and Don Ganem*

Howard Hughes Medical Institute and GW Hooper Foundation, Departments of Microbiology and Medicine, University of California, San Francisco, California 94143

Received 7 December 2008/ Accepted 6 March 2009

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.

* Corresponding author. Mailing address: Howard Hughes Medical Institute and GW Hooper Foundation, Departments of Microbiology and Medicine, University of California, San Francisco, CA 94143. Phone: (415) 476-2826. Fax: (415) 476-0939. E-mail: ganem{at}cgl.ucsf.edu

{triangledown} Published ahead of print on 11 March 2009.

{dagger} These authors contributed equally to this work.

Journal of Virology, May 2009, p. 5056-5066, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.02516-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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