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J. Biol. Chem., Vol. 280, Issue 44, 36935-36945, November 4, 2005

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Interaction of the Epstein-Barr Virus mRNA Export Factor EB2 with Human Spen Proteins SHARP, OTT1, and a Novel Member of the Family, OTT3, Links Spen Proteins with Splicing Regulation and mRNA Export^*

Edwige Hiriart1, Henri Gruffat, Monique Buisson2, Ivan Mikaelian34, Selina Keppler, Patrick Meresse, Thomas Mercher¶5, Olivier A. Bernard¶, Alain Sergeant4, and Evelyne Manet46

From the INSERM U412, ENS-Lyon, IFR 128 Biosciences Lyon Gerland, Laboratoire de Virologie Humaine, 46 Allée d'Italie, 69364 Lyon, France, FRE 2854 CNRS, UJR Laboratoire de Virologie Moléculaire et Structurale, Hybrisère, Domaine de la Merci, 38706 La Tronche, France, and ^¶INSERM E0210, Hôpital Necker, 149 Rue de Sèvres, 75743 Paris Cedex 15, France

The Epstein-Barr virus early protein EB2 (also called BMLF1, Mta, or SM), a protein absolutely required for the production of infectious virions, shares properties with mRNA export factors. By using a yeast two-hybrid screen, we have identified the human protein OTT3 as an EB2-interacting factor. OTT3 is a new member of the Spen (split end) family of proteins (huSHARP, huOTT1, DmSpen, and muMINT), which are characterized by several N-terminal RNA recognition motifs and a highly conserved C-terminal SPOC (Spen Paralog and Ortholog C-terminal) domain that, in the case of SHARP, has been shown to interact with SMRT/NCoR corepressors. OTT3 is ubiquitously expressed as a 120-kDa protein. Transfected OTT3 is a nonshuttling nuclear protein that co-localizes with co-transfected EB2. We also showed that EB2 interacts with the SPOC domains of both OTT1 and SHARP proteins. Although the OTT3 interaction domain maps within the 40 N-terminal amino acids of EB2, OTT1 and SHARP interact within the C-terminal half of the protein. Furthermore, we demonstrated that the capacity of the OTT3 and OTT1 SPOC domains to interact with SMRT and repress transcription is far weaker than that of SHARP. Thus there is no evidence for a role of OTT3 in transcriptional regulation. Most interestingly, however, we have found that OTT3 has a role in splicing regulation; OTT3 represses accumulation of the alternatively spliced -thalassemia mRNAs, but it has no effect on the -globin constitutively spliced mRNA. Thus our results suggested a new function for Spen proteins related to mRNA export and splicing.

Received for publication, February 15, 2005 , and in revised form, July 19, 2005.

^* This work was supported in part by INSERM and by Grant 3420 from the Association pour la Recherche Contre le Cancer (to A. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a Ministère de l'Education Nationale de la Recherche et de la Technologie fellowship and a grant from the Fondation pour la Recherche Medicale.

² Present address: CNRS FRE 2692, Génétique et Cancer, UCB Lyon I, Domaine Rockefeller, 8 Ave. Rockefeller, 69373 Cedex 08, Lyon, France.

³ Present address: Aptanomics SA, 181-203 Ave J. Jaurès, 69007 Lyon, France.

⁴ CNRS scientist.

⁵ Present address: D. G. Gilliland Laboratory, Brigham & Women's Hospital, Karp Family Research Bldg., 1 Blackfan Circle, Rm. 5007B, Boston, MA 02115.

⁶ To whom correspondence should be addressed: INSERM U412, ENS-Lyon, IFR 128 Biosciences Lyon Gerland, Laboratoire de Virologie Humaine, 46, Allée d'Italie, 69364 Lyon, Cedex 07, France. Tel.: 33-4-72-72-81-76; Fax: 33-4-72-72-80-80; E-mail: evelyne.manet{at}ens-lyon.fr.

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