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Journal of Virology, July 2009, p. 6739-6747, Vol. 83, No. 13
0022-538X/09/$08.00+0 doi:10.1128/JVI.02353-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 4 Targets MDM2 To Deregulate the p53 Tumor Suppressor Pathway
,
Hye-Ra Lee,1,2
Zsolt Toth,1
Young C. Shin,2
Jong-Soo Lee,1,2
Heesoon Chang,1,2
Wei Gu,3
Tae-Kwang Oh,4
Myung Hee Kim,4 and
Jae U. Jung1,2*
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Harlyne J. Norris Cancer Research Tower, 1450 Biggy Street, Los Angeles, California 90033,1 Department of Microbiology and Molecular Genetics and Tumor Virology Division, New England Primate Research Center, Harvard Medical School, 1 Pine Hill Drive, Southborough, Massachusetts 01772,2 Institute for Cancer Genetics and Department of Pathology, College of Physicians and Surgeons, Columbia University, 1130 St. Nicholas Avenue, New York, New York 10032,3 Systems Microbiology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, South Korea4
Received 11 November 2008/ Accepted 2 April 2009
Cells infected by viruses utilize interferon (IFN)-mediated and p53-mediated irreversible cell cycle arrest and apoptosis as part of the overall host surveillance mechanism to ultimately block viral replication and dissemination. Viruses, in turn, have evolved elaborate mechanisms to subvert IFN- and p53-mediated host innate immune responses. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes several viral IFN regulatory factors (vIRF1 to vIRF4) within a cluster of loci, their functions being primarily to inhibit host IFN-mediated innate immunity and deregulate p53-mediated cell growth control. Despite its significant homology and similar genomic location to other vIRFs, vIRF4 is distinctive, as it does not target and antagonize host IFN-mediated signal transduction. Here, we show that KSHV vIRF4 interacts with the murine double minute 2 (MDM2) E3 ubiquitin ligase, leading to the reduction of p53, a tumor suppressor, via proteasome-mediated degradation. The central region of vIRF4 is required for its interaction with MDM2, which led to the suppression of MDM2 autoubiquitination and, thereby, a dramatic increase in MDM2 stability. Consequently, vIRF4 expression markedly enhanced p53 ubiquitination and degradation, effectively suppressing p53-mediated apoptosis. These results indicate that KSHV vIRF4 targets and stabilizes the MDM2 E3 ubiquitin ligase to facilitate the proteasome-mediated degradation of p53, perhaps to circumvent host growth surveillance and facilitate viral replication in infected cells. Taken together, the indications are that the downregulation of p53-mediated cell growth control is a common characteristic of the four KSHV vIRFs and that p53 is indeed a key factor in the host's immune surveillance program against viral infections.
* Corresponding author. Mailing address: Department of Molecular Microbiology and Immunology, University of Southern California, Harlyne J. Norris Cancer Research Tower, Room 5517, 1450 Biggy Street, Los Angeles, CA 90033. Phone: (323) 442-1713. Fax: (323) 442-1721. E-mail: jaeujung{at}usc.edu
Published ahead of print on 15 April 2009.
Supplemental material for this article may be found at http://jvi.asm.org/.
Journal of Virology, July 2009, p. 6739-6747, Vol. 83, No. 13
0022-538X/09/$08.00+0 doi:10.1128/JVI.02353-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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