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Journal of Virology, September 2005, p. 11135-11141, Vol. 79, No. 17
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.17.11135-11141.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Ubiquitylation of Cdk9 by Skp2 Facilitates Optimal Tat Transactivation

Matjaz Barboric,1 Fan Zhang,1 Mojca Besenicar,2 Ana Plemenitas,3 and B. Matija Peterlin1*

Rosalind Russell Medical Research Center, Departments of Medicine, Microbiology and Immunology, University of California at San Francisco, San Francisco, California 94143-0703,1 Institute of Biochemistry, Medical Faculty of the University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia,3 Department of Biology, Biotechnical Faculty, University of Ljubljana, Vecna pot 111, 1000 Ljubljana, Slovenia2

Received 23 April 2004/ Accepted 26 May 2005

By recruiting the positive transcriptional elongation factor b (P-TEFb) to paused RNA polymerase II, the transactivator Tat stimulates transcriptional elongation of the human immunodeficiency virus type 1 (HIV-1) genome. We found that cyclin-dependent kinase 9 (Cdk9), the catalytic subunit of P-TEFb, is ubiquitylated in vivo. This ubiquitylation depended on the Skp1/Cul1/F-box protein E3 ubiquitin ligase Skp2. Likewise, Tat required Skp2 since its transactivation of the HIV-1 long terminal repeat decreased in primary mouse embryonic fibroblasts, which lacked Skp2. The ubiquitylation of Cdk9 by Skp2 facilitated the formation of the ternary complex between P-TEFb, Tat, and transactivation response element. Thus, our findings underscore the requirement of ubiquitylation for the coactivator function in regulating HIV-1 transcriptional elongation.

* Corresponding author. Mailing address: 533 Parnassus Ave., San Francisco, CA 94143. Phone: (415) 502-1902. Fax: (415) 502-1901. E-mail: matija{at}itsa.ucsf.edu.

Journal of Virology, September 2005, p. 11135-11141, Vol. 79, No. 17
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.17.11135-11141.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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