title: Tat competes with HEXIM1 to increase the active pool of P-TEFb for HIV-1 transcription.
abstract: Human immunodeficiency virus type 1 (HIV-1) transcriptional transactivator (Tat) recruits the positive transcription elongation factor b (P-TEFb) to the viral promoter. Consisting of cyclin dependent kinase 9 (Cdk9) and cyclin T1, P-TEFb phosphorylates RNA polymerase II and the negative transcription elongation factor to stimulate the elongation of HIV-1 genes. A major fraction of nuclear P-TEFb is sequestered into a transcriptionally inactive 7SK small nuclear ribonucleoprotein (snRNP) by the coordinated actions of the 7SK small nuclear RNA (snRNA) and hexamethylene bisacetamide (HMBA) induced protein 1 (HEXIM1). In this study, we demonstrate that Tat prevents the formation of and also releases P-TEFb from the 7SK snRNP in vitro and in vivo. This ability of Tat depends on the integrity of its N-terminal activation domain and stems from the high affinity interaction between Tat and cyclin T1, which allows Tat to directly displace HEXIM1 from cyclin T1. Furthermore, we find that in contrast to the Tat-independent activation of the HIV-1 promoter, Tat-dependent HIV-1 transcription is largely insensitive to the inhibition by HEXIM1. Finally, primary blood lymphocytes display a reduced amount of the endogenous 7SK snRNP upon HIV-1 infection. All these data are consistent with the model that Tat not only recruits but also increases the active pool of P-TEFb for efficient HIV-1 transcription.
authors.affiliation: Department of Medicine, Rosalind Russell Medical Research Center, University of California at San Francisco, San Francisco, CA 94143-0703, USA.
authors.forename: Matjaz
authors.initials: M
authors.lastname: Barboric
authors.forename: Jasper H N
authors.initials: JH
authors.lastname: Yik
authors.forename: Nadine
authors.initials: N
authors.lastname: Czudnochowski
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Yang
authors.forename: Ruichuan
authors.initials: R
authors.lastname: Chen
authors.forename: Xavier
authors.initials: X
authors.lastname: Contreras
authors.forename: Matthias
authors.initials: M
authors.lastname: Geyer
authors.forename: B
authors.initials: B
authors.lastname: Matija Peterlin
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhou
mesh_terms: D001667:Binding, Competitive; D056906:Cyclin T; D016213:Cyclins; D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism / Q000821:virology; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017411:Ribonucleoproteins, Small Nuclear / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: C503684:CCNT1 protein, human; D056906:Cyclin T; D016213:Cyclins; D015696:Gene Products, tat; C476123:HEXIM1 protein, human; D016601:RNA-Binding Proteins; D017411:Ribonucleoproteins, Small Nuclear; D014157:Transcription Factors; D054322:tat Gene Products, Human Immunodeficiency Virus; D042925:Positive Transcriptional Elongation Factor B