Nuclear Protein Phosphatase-1 Regulates HIV-1 Transcription

Ammosova, Tatyana; Jerebtsova, Marina; Beullens, Monique; Voloshin, Yaroslav; Ray, Patricio E.; Kumar, Ajit; Bollen, Mathieu; Nekhai, Sergeï

doi:10.1074/jbc.m300521200

Cited by 51 publications

(83 citation statements)

References 30 publications

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“…Section 1734 solely to indicate this fact. 1 PP1, and the inhibition is reversed by co-expression of PP1␥ (20). In the present paper we show that Tat binds to PP1 in vitro and in vivo.…”

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confidence: 68%

“…previous data (20), showing that PP1␥ is necessary for Tat-mediated HIV-1 transcription in cultured cells, we found that the transient expression in HEK293T cells of a catalytically dead mutant of PP1, i.e. PP1␥-D64N, inhibited the Tat-activated transcription of the HIV-1 LTR by 3-fold (Fig.…”

Section: Pp1 Is a Critical Factor For Hiv-1 Transcription-in Accordanmentioning

confidence: 98%

“…Our studies showed that PP1 is also a positive regulator of HIV-1 transcription in vitro (18,19) and in vivo (20). Indeed, in a previous study we showed that inhibition of nuclear PP1 potently inhibited Tat-induced transcription (20). We concluded that the inhibition was because of sequestration of PP1 because the inhibition was alleviated by the co-expression of PP1 (20).…”

mentioning

confidence: 88%

“…Thus, PP2A might positively regulate HIV-1 transcription. Our studies showed that PP1 is also a positive regulator of HIV-1 transcription in vitro (18,19) and in vivo (20). Indeed, in a previous study we showed that inhibition of nuclear PP1 potently inhibited Tat-induced transcription (20).…”

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confidence: 95%

“…Indeed, in a previous study we showed that inhibition of nuclear PP1 potently inhibited Tat-induced transcription (20). We concluded that the inhibition was because of sequestration of PP1 because the inhibition was alleviated by the co-expression of PP1 (20). We recently compared contributions of PP2A and PP1 to the dephosphorylation of CDK9 and to HIV-1 transcription in vitro and in vivo and found that although PP2A dephosphorylates CDK9 in vitro, in cultured cells PP1 is likely to dephosphorylate CDK9 and contribute to the regulation of HIV-1 transcription (21).…”

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confidence: 99%

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Nuclear Targeting of Protein Phosphatase-1 by HIV-1 Tat Protein

Ammosova

Jerebtsova

Beullens

et al. 2005

Journal of Biological Chemistry

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Transcription of human immunodeficiency virus (HIV)-1 genesis activated by HIV-1 Tat protein, which induces phosphorylation of the C-terminal domain of RNA polymerase-II by CDK9/cyclin T1. We previously showed that Tat-induced HIV-1 transcription is regulated by protein phosphatase-1 (PP1). In the present study we demonstrate that Tat interacts with PP1 and that disruption of this interaction prevents induction of HIV-1 transcription. We show that PP1 interacts with Tat in part through the binding of Val 36 and Phe 38 of Tat to PP1 and that Tat is involved in the nuclear and subnuclear targeting of PP1. The PP1 binding mutant Tat-V36A/ F38A displayed a decreased affinity for PP1 and was a poor activator of HIV-1 transcription. Surprisingly, Tat-Q35R mutant that had a higher affinity for PP1 was also a poor activator of HIV-1 transcription, because strong PP1 binding competed out binding of Tat to CDK9/cyclin T1. Our results suggest that Tat might function as a nuclear regulator of PP1 and that interaction of Tat with PP1 is critical for activation of HIV-1 transcription by Tat. Human immunodeficiency virus type 1 (HIV-1)3 is a retrovirus that encodes transcriptional activator (Tat) protein. The activation domain of Tat (amino acids 1-48) interacts with host cell factors, whereas the positively charged RNA-binding domain (amino acids 49 -57) interacts with HIV-1 transactivation response (TAR) RNA (1). In cell-free transcription assays Tat induces elongation of transcription (2, 3). In vivo, Tat also induces initiation of transcription from the integrated HIV-1 promoter (4 -6). In a recent study Tat was shown to stimulate formation of a transcription complex containing TATA box-binding protein but not TATA box-binding protein-associated factors, thus indicating that Tat may enhance initiation of transcription (4). This finding apparently agrees with the early observation that Tat binds directly to the TATA box-binding protein-containing basal transcription factor TFIID (7). Tat activates HIV-1 transcription by recruiting transcriptional coactivators that include positive transcription elongation factor b, containing CDK9/cyclin T1, an RNA polymerase II CTD kinase (3,8,9) and histone acetyltransferases (10 -12). Whereas positive transcription elongation factor b induces HIV-1 transcription from non-integrated HIV-1 template (3,8,9), histone acetyltransferases allow induction of integrated HIV-1 provirus (10 -12). In contrast to the well defined role of protein kinases, the role of protein phosphatases in Tat-mediated HIV-1 transcription is less well understood. FCP1, a CTD phosphatase that dephosphorylates Ser-2 during elongation of transcription (13), is inhibited by Tat and this inhibition may alleviate FCP1-mediated pausing of transcription (14,15). In addition to FCP1, PP2A and PP1 were also shown to be involved in the regulation of HIV-1 transcription. Disregulation of cellular enzymatic activity of PP2A inhibited Tat-induced HIV-1 transcription (16). Expression of the catalytic subunit of PP2A enhanced activa...

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“…Section 1734 solely to indicate this fact. 1 PP1, and the inhibition is reversed by co-expression of PP1␥ (20). In the present paper we show that Tat binds to PP1 in vitro and in vivo.…”

mentioning

confidence: 68%

Section: Pp1 Is a Critical Factor For Hiv-1 Transcription-in Accordanmentioning

confidence: 98%

mentioning

confidence: 88%

mentioning

confidence: 95%

mentioning

confidence: 99%

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Nuclear Targeting of Protein Phosphatase-1 by HIV-1 Tat Protein

Ammosova

Jerebtsova

Beullens

et al. 2005

Journal of Biological Chemistry

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Regulation of HIV‐1 transcription at 3% versus 21% oxygen concentration

Charles

Ammosova

Cardenas

et al. 2009

Journal Cellular Physiology

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HIV transcription is induced by the HIV-1 Tat protein, in concert with cellular co-factors including CDK9, CDK2, NF-κB, and others. The cells of most of the body’s organs are exposed to ~3–6% oxygen, but most in vitro studies of HIV replication are conducted at 21% oxygen. We hypothesized that activities of host cell factors involved in HIV-1 replication may differ at 3% versus 21% O2, and that such differences may affect HIV-1 replication. Here we show that Tat-induced HIV-1 transcription was reduced at 3% O2 compared to 21% O2. HIV-1 replication was also reduced in acutely or chronically infected cells cultured at 3% O2 compared to 21% O2. This reduction was not due the decreased cell growth or increased cellular toxicity and also not due to the induction of hypoxic response. At 3% O2, the activity of CDK9/cyclin T1 was inhibited and Sp1 activity was reduced, whereas the activity of other host cell factors such as CDK2 or NF-κB was not affected. CDK9-specific inhibitor ARC was much less efficient at 3% compared to 21% O2 and also expression of CDK9/cyclin T1-dependent IκB inhibitor α was repressed. Our results suggest that lower HIV-1 transcription at 3% O2 compared to 21% O2 may be mediated by lower activity of CDK9/cyclin T1 and Sp1 at 3% O2 and that additional host cell factors such as CDK2 and NF-κB might be major regulators of HIV-1 transcription at low O2 concentrations.

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The regulation of HIV-1 transcription: Molecular targets for chemotherapeutic intervention

2006

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The regulation of transcription of the human immunodeficiency virus (HIV) is a complex event that requires the cooperative action of both viral and cellular components. In latently infected resting CD4(+) T cells HIV-1 transcription seems to be repressed by deacetylation events mediated by histone deacetylases (HDACs). Upon reactivation of HIV-1 from latency, HDACs are displaced in response to the recruitment of histone acetyltransferases (HATs) by NF-kappaB or the viral transcriptional activator Tat and result in multiple acetylation events. Following chromatin remodeling of the viral promoter region, transcription is initiated and leads to the formation of the TAR element. The complex of Tat with p-TEFb then binds the loop structures of TAR RNA thereby positioning CDK9 to phosphorylate the cellular RNA polymerase II. The Tat-TAR-dependent phosphorylation of RNA polymerase II plays an important role in transcriptional elongation as well as in other post-transcriptional events. As such, targeting of Tat protein (and/or cellular cofactors) provide an interesting perspective for therapeutic intervention in the HIV replicative cycle and may afford lifetime control of the HIV infection.

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Nuclear Protein Phosphatase-1 Regulates HIV-1 Transcription

Abstract: We recently reported that protein phosphatase 1 (PP1) dephosphorylates RNA polymerase II C-terminal repeats and regulates HIV-1 transcription in vitro. Here we provide evidence that PP1 is also required for Tat

Cited by 51 publications

References 30 publications

Nuclear Targeting of Protein Phosphatase-1 by HIV-1 Tat Protein

Nuclear Targeting of Protein Phosphatase-1 by HIV-1 Tat Protein

Regulation of HIV‐1 transcription at 3% versus 21% oxygen concentration

The regulation of HIV-1 transcription: Molecular targets for chemotherapeutic intervention

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