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Journal of Virology, April 2006, p. 3189-3204, Vol. 80, No. 7
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.7.3189-3204.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Acetylated Tat Regulates Human Immunodeficiency Virus Type 1 Splicing through Its Interaction with the Splicing Regulator p32

Reem Berro,1 Kylene Kehn,2 Cynthia de la Fuente,2 Anne Pumfery,2,{dagger} Richard Adair,3,{ddagger} John Wade,4 Anamaris M. Colberg-Poley,3 John Hiscott,5 and Fatah Kashanchi1,2,6*

Genetics Program, The George Washington University, Washington, D.C. 20037,1 Department of Biochemistry and Molecular Biology, The George Washington University School of Medicine, Washington, D.C. 20037,2 Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, Washington, D.C. 20010,3 Howard Florey Institute, University of Melbourne, Victoria 3010, Australia,4 Lady Davis Institute for Medical Research, McGill University, Montreal, Canada,5 The Institute for Genomic Research, Rockville, Maryland 208506

Received 5 July 2005/ Accepted 10 January 2006

The human immunodeficiency virus type 1 (HIV-1) potent transactivator Tat protein mediates pleiotropic effects on various cell functions. Posttranslational modification of Tat affects its activity during viral transcription. Tat binds to TAR and subsequently becomes acetylated on lysine residues by histone acetyltransferases. Novel protein-protein interaction domains on acetylated Tat are then established, which are necessary for both sustained transcriptional activation of the HIV-1 promoter and viral transcription elongation. In this study, we investigated the identity of proteins that preferentially bound acetylated Tat. Using a proteomic approach, we identified a number of proteins that preferentially bound AcTat, among which p32, a cofactor of splicing factor ASF/SF-2, was identified. We found that p32 was recruited to the HIV-1 genome, suggesting a mechanism by which acetylation of Tat may inhibit HIV-1 splicing needed for the production of full-length transcripts. Using Tat from different clades, harboring a different number of acetylation sites, as well as Tat mutated at lysine residues, we demonstrated that Tat acetylation affected splicing in vivo. Finally, using confocal microscopy, we found that p32 and Tat colocalize in vivo in HIV-1-infected cells.

* Corresponding author. Mailing address: The George Washington University, 2300 I St., NW, Ross Hall, Room 551, Washington, DC 20037. Phone: (202) 994-1781. Fax: (202) 994-1780. E-mail: bcmfxk{at}gwumc.edu.

{dagger} Present address: Department of Biology, Seton Hall University, South Orange, NJ 07079.

{ddagger} Present address: MRC Virology Unit, Institute of Virology, Glasgow, Scotland, United Kingdom.

Journal of Virology, April 2006, p. 3189-3204, Vol. 80, No. 7
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.7.3189-3204.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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