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Journal of Virology, February 2008, p. 1679-1687, Vol. 82, No. 4
0022-538X/08/$08.00+0     doi:10.1128/JVI.02142-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Autorepression of Epstein-Barr Virus Nuclear Antigen 1 Expression by Inhibition of Pre-mRNA Processing{triangledown}

Mikio Yoshioka,1,{dagger} Michelle M. Crum,1,2 and Jeffery T. Sample1,2*

Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 38105,1 Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee 381632

Received 28 September 2007/ Accepted 28 November 2007

Epstein-Barr virus (EBV) latent infection, and its associated oncogenic potential, is dependent on genome maintenance functions of EBV nuclear antigen 1 (EBNA-1), one of six EBNAs expressed from a common promoter (Wp and then Cp) upon infection of naive B cells. Subsequent host-mediated silencing, however, necessitates the expression of EBNA-1 from the EBNA-1-specific promoter Qp to ensure against genome loss during cell division, including EBV-associated malignancy. Here we addressed the mechanism by which EBNA-1 represses Qp through binding downstream of the transcription start site and the role of this autoregulatory function in EBV latency. Our results revealed that EBNA-1 does not inhibit transcription from Qp, as previously predicted, but acts post- or cotranscriptionally to block the processing of primary transcripts. This does not, however, require the RGG motifs responsible for strong but nonspecific RNA binding by EBNA-1. Within isogenic B-cell lines using either Cp/Wp or Qp, EBNA-1 occupancy of Qp is equivalent, suggesting that autoregulation occurs, albeit to different degrees, during full and restricted EBV latency programs. Finally, in cell lines using Cp or Wp for EBNA expression, unprocessed transcripts from Qp are detectable in the absence of corresponding mRNAs, providing further evidence that this novel mechanism of EBNA-1 action functions during latency. This posttranscriptional mechanism of regulation would provide an efficient means to monitor and regulate EBNA-1 expression from Qp, ensuring levels adequate for genome maintenance but, perhaps more importantly, below an immunogenic threshold above which latently infected cells may be at risk for elimination by EBNA-1-specific cytotoxic T cells.

* Corresponding author. Present address: Department of Microbiology and Immunology—H107, The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, 500 University Dr., P.O. Box 850, Hershey, PA 17033. Phone: (717) 531-0003, ext. 287151. Fax: (717) 531-6522. E-mail: jsample{at}hmc.psu.edu

{triangledown} Published ahead of print on 12 December 2007.

{dagger} Present address: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine and The Milton S. Hershey Medical Center, Hershey, PA 17033.

Journal of Virology, February 2008, p. 1679-1687, Vol. 82, No. 4
0022-538X/08/$08.00+0     doi:10.1128/JVI.02142-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Dresang, L. R., Vereide, D. T., Sugden, B. (2009). Identifying Sites Bound by Epstein-Barr Virus Nuclear Antigen 1 (EBNA1) in the Human Genome: Defining a Position-Weighted Matrix To Predict Sites Bound by EBNA1 in Viral Genomes. J. Virol. 83: 2930-2940 [Abstract] [Full Text]  


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