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Originally published In Press as doi:10.1074/jbc.M208954200 on December 9, 2002

J. Biol. Chem., Vol. 278, Issue 7, 4440-4448, February 14, 2003
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The TAR RNA-binding Protein, TRBP, Stimulates the Expression of TAR-containing RNAs in Vitro and in Vivo Independently of Its Ability to Inhibit the dsRNA-dependent Kinase PKR*

Dominique DorinDagger §, Marion C. Bonnet, Sylvie Bannwarth||**, Anne Gatignol||Dagger Dagger §§, Eliane F. Meurs¶¶, and Catherine VaqueroDagger ¶¶

From Dagger  INSERM U511, Hôpital La Pitié-Salpêtrière, 75643 Paris Cedex 13, France,  Unité des Hépacivirus, Institut Pasteur, 75724 Paris Cedex 15, France, the || Molecular Oncology Group/McGill AIDS Centre, Lady Davis Institute for Medical Research, 3755 Côte Ste Catherine, Montréal, Québec H3T 1E2, Canada, and the Dagger Dagger  Department of Medicine and Microbiology & Immunology, McGill University, Montréal, Québec H3A 2B4, Canada

TRBP (HIV-1 transactivating response (TAR) RNA-binding protein) and PKR, the interferon-induced dsRNA-regulated protein kinase, contain two dsRNA binding domains. They both bind to HIV-1 TAR RNAs through different sites. Binding to dsRNA activates PKR that phosphorylates the eukaryotic initiation factor eIF-2alpha leading to protein synthesis inhibition. TRBP and PKR can heterodimerize, which inhibits the kinase function of PKR and has a positive effect on HIV-1 expression. In this study, an in vitro reticulocyte assay revealed the poor expression of TAR containing CAT RNAs compared with CAT RNAs. Addition of TRBP restored translation efficiency of TAR-CAT RNA and decreased the phosphorylation status of eIF-2alpha , confirming its role as a PKR inhibitor. Unexpectedly, eIF-2alpha was phosphorylated in the presence of TAR-CAT as well as CAT RNA devoid of the TAR structure. TRBP inhibited eIF-2alpha phosphorylation in both cases, suggesting that it restores the translation of TAR-CAT RNA independently and in addition to its ability to inhibit PKR. TRBP activity on gene expression was then analyzed in a PKR-free environment using PKR-deficient murine embryo fibroblasts. In a transient reporter gene assay, TRBP stimulated the expression of a TAR-containing luciferase 3.8-fold whereas the reporter gene with mutated TAR structures or devoid of TAR was stimulated 1.5- to 2.4-fold. Overall, the activity of TRBP2 was higher when the 5'-end of the mRNA was structured and was mediated independently by each dsRBD in TRBP. Increasing concentrations of TRBP showed no significant modification of the luciferase RNA levels, suggesting that TRBP stimulates translation of TAR-containing RNAs. Therefore, TRBP is an important cellular factor for efficient translation of dsRNA containing transcripts, both by inhibiting PKR and in a PKR-independent pathway.

* This work was supported by INSERM, by grants from the Agence Nationale de la Recherche sur le SIDA (to C. V. and E. F. M.), and by Grant HOP-38112 from the Medical Research Council of Canada (to A. G.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Supported by Agence Nationale de Recherche sur le SIDA.

** Supported by a Canadian Institutes of Health Research postdoctoral fellowship.

§§ Research Scientist from the Fond de la Recherche en Santé du Québec.

¶¶ To whom correspondence may be addressed. Tel.: 33-1-40-77-81-11; Fax: 33-1-45-83-88-58; E-mail: vaquero@idf.ext.jussieu.fr (to C. V.) or Tel.: 33-1-45-68-87-77; Fax: 33-1-40-61-30-12; E-mail: emeurs@pasteur.fr (to E. F. M.).

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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