Identification of a Cellular Protein That Interacts and Synergizes with the RTA (ORF50) Protein of Kaposi's Sarcoma-Associated Herpesvirus in Transcriptional Activation

doi:10.1128/JVI.75.24.11961-11973.2001

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Journal of Virology, December 2001, p. 11961-11973, Vol. 75, No. 24
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.24.11961-11973.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Identification of a Cellular Protein That Interacts and Synergizes with the RTA (ORF50) Protein of Kaposi's Sarcoma-Associated Herpesvirus in Transcriptional Activation

Shizhen Wang,¹^,²^,³ Shuhong Liu,¹^,² Ming-Hoi Wu,¹^,² Yunqi Geng,³ and Charles Wood¹^,²^,^*

Nebraska Center for Virology¹ and School of Biological Sciences,² University of Nebraska, Lincoln, Nebraska 68588, and College of Life Sciences, Nankai University, Tianjin 300071, People's Republic of China³

Received 13 June 2001/Accepted 6 September 2001

Lytic reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8, from latency requires transcriptionaltransactivation by the viral protein RTA encoded by the ORF50gene. Very little is known about how RTA functions and the cellularfactors that may be involved in its transactivation function.Using the yeast two-hybrid system, we have identified a humancellular protein that can interact with KSHV RTA. The cellularprotein, referred to as the human hypothetical protein MGC2663by GenBank, is encoded by human chromosome 19. This protein is554 amino acids (aa) in size and displays sequence similaritywith members of the Krueppel-associated box-zinc finger proteins(KRAB-ZFPs). MGC2663 expression could be detected in all primatecell lines tested, and its expression level was neither stimulatednor inhibited by RTA. MGC2663 specifically synergizes with RTAto activate viral transcription, and overexpression of MGC2663in the presence of RTA further enhances RTA transactivation ofseveral viral promoters that were identified as targets for RTA.Coimmunoprecipitation and pull-down assays further demonstratedthat MGC2663 interacts with RTA both in vivo and in vitro, andthe N-terminal 273 aa of KSHV RTA and the potential zinc fingerdomain of MGC2663 are required for their interaction. Our resultsindicate that this novel human cellular protein, MGC2663, namedK-RBP (KSHV RTA binding protein) due to its RTA binding feature,specifically interacts with the KSHV RTA protein and functionsas a cellular RTA cofactor to activate viral gene expression.Though its normal cellular function needs to be further studied,K-RBP may play a significant role in mediating RTA transactivationinvivo.

^* Corresponding author. Mailing address: School of Biological Sciences, University of Nebraska, E249 Beadle Center, P.O. Box880666, Lincoln, NE 68588-0666. Phone: (402) 472-4550. Fax: (402)472-8722. E-mail: cwood1{at}unl.edu.

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