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Journal of Virology, July 2000, p. 6068-6076, Vol. 74, No. 13
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Epstein-Barr Virus EB2 Protein Exports Unspliced RNA via a Crm-1-Independent Pathway

Géraldine Farjot,1 Monique Buisson,1 Madeleine Duc Dodon,2 Louis Gazzolo,2 Alain Sergeant,1 and Ivan Mikaelian1,*

U412 INSERM, ENS-Lyon,1 and Immuno-Virologie Moléculaire et Cellulaire, UMR 5537, Centre National de la Recherche Scientifique-Université Claude Bernard Lyon 1, Faculté de Médecine Lyon-RTH Laennec,2 Lyon, France

Received 7 January 2000/Accepted 4 April 2000

Human herpesviruses encode posttranscriptional activators that are believed to up-regulate viral replication by facilitating early and late gene expression. We have reported previously that the Epstein-Barr virus protein EB2 (also called M or SM) promotes nuclear export of RNAs that are poor substrates for spliceosome assembly, an effect that closely resembles the human immunodeficiency virus type 1 Rev-dependent nuclear export of unspliced viral RNA. Here we present experimental data showing that EB2 efficiently promotes the nuclear export of unspliced RNA expressed from a Rev reporter construct. Site-directed mutagenesis as well as domain swapping experiments indicate that a leucine-rich region found in the EB2 protein, which matches the consensus sequence for the leucine-rich nuclear export signal, is not a nuclear export signal per se. Accordingly, leptomycin B (LMB), a specific Crm-1 inhibitor, impairs Rev- but not EB2-dependent nuclear export of unspliced RNA. Moreover, EB2 nucleocytoplasmic shuttling visualized by a heterokaryon assay is, unlike Rev shuttling, not affected by LMB. We also show that overexpression of an N-terminal deletion mutant of Nup214/can, a major nucleoporin of the nuclear pore complex involved in several aspects of nuclear transport, blocks both Rev- and EB2-dependent nuclear export of RNA. These results strongly suggest that EB2 nuclear export of unspliced RNA is mediated by a Crm-1-independent pathway.

* Corresponding author. Mailing address: U412 INSERM, ENS-Lyon, 46 allée d'Italie, 69364 Lyon Cedex 07, France. Phone: (33) 4 72 72 81 75. Fax: (33) 4 72 72 87 77. E-mail: ivan.mikaelian{at}ens-lyon.fr.

Journal of Virology, July 2000, p. 6068-6076, Vol. 74, No. 13
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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