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Autorepression of Epstein-Barr virus nuclear antigen 1 expression by inhibition of pre-mRNA processing.
J Virol. 2008 Feb; 82(4):1679-87.JV

Abstract

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.

Authors+Show Affiliations

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, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18077719

Citation

Yoshioka, Mikio, et al. "Autorepression of Epstein-Barr Virus Nuclear Antigen 1 Expression By Inhibition of pre-mRNA Processing." Journal of Virology, vol. 82, no. 4, 2008, pp. 1679-87.
Yoshioka M, Crum MM, Sample JT. Autorepression of Epstein-Barr virus nuclear antigen 1 expression by inhibition of pre-mRNA processing. J Virol. 2008;82(4):1679-87.
Yoshioka, M., Crum, M. M., & Sample, J. T. (2008). Autorepression of Epstein-Barr virus nuclear antigen 1 expression by inhibition of pre-mRNA processing. Journal of Virology, 82(4), 1679-87.
Yoshioka M, Crum MM, Sample JT. Autorepression of Epstein-Barr Virus Nuclear Antigen 1 Expression By Inhibition of pre-mRNA Processing. J Virol. 2008;82(4):1679-87. PubMed PMID: 18077719.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Autorepression of Epstein-Barr virus nuclear antigen 1 expression by inhibition of pre-mRNA processing. AU - Yoshioka,Mikio, AU - Crum,Michelle M, AU - Sample,Jeffery T, Y1 - 2007/12/12/ PY - 2007/12/14/pubmed PY - 2008/3/6/medline PY - 2007/12/14/entrez SP - 1679 EP - 87 JF - Journal of virology JO - J Virol VL - 82 IS - 4 N2 - 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. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/18077719/Autorepression_of_Epstein_Barr_virus_nuclear_antigen_1_expression_by_inhibition_of_pre_mRNA_processing_ L2 - http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=18077719 DB - PRIME DP - Unbound Medicine ER -