Ubiquitylation of Cdk9 by Skp2 facilitates optimal Tat transactivation.
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.
Barboric
Matjaz
M
Rosalind Russell Medical Research Center, Department of Medicine, University of California, San Francisco, 94143, USA.
Zhang
Fan
F
Besenicar
Mojca
M
Plemenitas
Ana
A
Peterlin
B Matija
BM
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D015533:Transcriptional Activation; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D044786:S-Phase Kinase-Associated Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D042863:Cyclin-Dependent Kinase 9