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Journal of Virology, January 2001, p. 90-99, Vol. 75, No. 1
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.1.90-99.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Amino Acids of Epstein-Barr Virus Nuclear Antigen 3A Essential for Repression of Jkappa -Mediated Transcription and Their Evolutionary Conservation

Rozenn Dalbiès-Tran,1 Evelyn Stigger-Rosser,1 Travis Dotson,1 and Clare E. Sample1,2,*

Program in Viral Oncogenesis and Tumor Immunology, Department of Virology and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105,1 and Department of Pathology, University of Tennessee College of Medicine, Memphis, Tennessee 381632

Received 18 April 2000/Accepted 18 September 2000

Epstein-Barr virus (EBV) nuclear antigen 3A (EBNA-3A) is essential for virus-mediated immortalization of B lymphocytes in vitro and is believed to regulate transcription of cellular and/or viral genes. One known mechanism of regulation is through its interaction with the cellular transcription factor Jkappa . This interaction downregulates transcription mediated by EBNA-2 and Jkappa . To identify the amino acids that play a role in this interaction, we have generated mutant EBNA-3A proteins. A mutant EBNA-3A protein in which alanine residues were substituted for amino acids 199, 200, and 202 no longer downregulated transcription. Surprisingly, this mutant protein remained able to coimmunoprecipitate with Jkappa . Using a reporter gene assay based on the recruitment of Jkappa by various regions spanning EBNA-3A, we have shown that this mutation abolished binding of Jkappa to the N-proximal region (amino acids 125 to 222) and that no other region of EBNA-3A alone was sufficient to mediate an association with Jkappa . To determine the biological significance of the interaction of EBNA-3A with Jkappa , we have studied its conservation in the simian lymphocryptovirus herpesvirus papio (HVP) by cloning HVP-3A, the homolog of EBNA-3A encoded by this virus. This 903-amino-acid protein exhibited 37% identity with its EBV counterpart, mainly within the amino-terminal half. HVP-3A also interacted with Jkappa through a region located between amino acids 127 and 223 and also repressed transcription mediated through EBNA-2 and Jkappa . The evolutionary conservation of this function, in proteins that have otherwise significantly diverged, argues strongly for an important biological role in virus-mediated immortalization of B lymphocytes.

* Corresponding author. Mailing address: Department of Virology and Molecular Biology, St. Jude Children's Research Hospital, 332 N. Lauderdale St., Memphis, TN 38105. Phone: (901) 495-3416. Fax: (901) 523-2622. E-mail: clare.sample{at}stjude.org.

Journal of Virology, January 2001, p. 90-99, Vol. 75, No. 1
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.1.90-99.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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