Phosphorylation of HIV-1 Tat by CDK2 in HIV-1 transcription

Ammosova, Tatyana; Berro, Reem; Jerebtsova, Marina; Jackson, Angela; Charles, Sharroya; Klase, Zachary; Southerland, William M.; Gordeuk, Victor R.; Kashanchi, Fatah; Nekhai, Sergeï

doi:10.1186/1742-4690-3-78

Cited by 82 publications

(66 citation statements)

References 54 publications

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“…Tat activity is altered by cellular modification factors such as p300, p300/CBP-associating factor (PCAF), Hdm2, Hexim1, and SKIP (20)(21)(22)(23). Tat phosphorylation by PKR (24) and CDK2 (25) has also been reported, and phosphorylation of Tat by PKR at three Ser/Thr sites (S62, T64, and S68) was shown to increase Tat-Tatresponsive region (TAR) binding and enhance transcription (26). However, the detailed molecular mechanisms underlying host restriction of HIV-1 replication via p53/PKR-mediated Tat phosphorylation and inactivation after HIV-1 infection are largely unknown.…”

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confidence: 99%

p53-Derived Host Restriction of HIV-1 Replication by Protein Kinase R-Mediated Tat Phosphorylation and Inactivation

Yoon

Kim

Byeon

et al. 2015

J Virol

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Tumor suppressor p53 has been suggested to be a host restriction factor against HIV-1 replication, but the detailed molecular mechanism has remained elusive for decades. Here, we demonstrate that p53-mediated HIV-1 suppression is attributed to double-stranded RNA (dsRNA)-dependent protein kinase (PKR)-mediated HIV-1 trans-activator (Tat) phosphorylation and inactivation. p53 silencing significantly enhanced HIV-1 replication in infected cells. Ectopic expression of p53 suppressed Tat activity, which was rescued by PKR silencing. In addition, ectopic expression of PKR abolished Tat activity in p53 ؊/؊ and eIF2␣ CA cells. Finally, we found that HIV-1 infection activates p53, followed by the induction and activation of PKR. PKR directly interacted with HIV-1 Tat and phosphorylates the first exon of Tat exclusively at five Ser/Thr residues (T23, T40, S46, S62, and S68), which inhibits Tat-mediated provirus transcription in three critical steps: (i) phosphorylation near the arginine-rich motif (ARM) inhibits Tat translocation into the nucleus, (ii) accumulation of Tat phosphorylation abolishes Tat-Tat-responsive region (TAR) binding, and (iii) Tat phosphorylation at T23 and/or T40 obliterates the Tat-cyclin T1 interaction. These five Ser/Thr sites on Tat were highly conserved in HIV-1 strains prevalent in Europe and the United States. Taken together, our findings indicate that p53-derived host restriction of HIV-1 replication is likely attributable, at least in part, to a noncanonical p53/PKR/Tat phosphorylation and inactivation pathway in HIV-1 infection and AIDS pathogenesis. IMPORTANCEHIV-1-mediated disease progression to AIDS lasts for years to decades after primary infection. Host restriction and associated viral latency have been studied for several decades. p53 has been suggested as an important host restriction factor against HIV-1 replication. However, the detailed molecular mechanism is still unclear. In the present study, we found that the p53-mediated HIV-1 restriction is attributed to a p53/PKR/Tat-inactivation pathway. HIV-1 infection activated p53, which subsequently induced PKR expression and activation. PKR directly phosphorylated Tat exclusively at five specific Ser/Thr residues, which was accompanied by significant suppression of HIV-1 replication. Accumulation of Tat phosphorylation at these sites inhibited Tat function by blocking Tat nuclear localization, Tat binding to TAR, and Tat-cyclin T1 interaction. Our findings provide a better understanding of the p53-derived host restriction mechanism against HIV-1 replication in AIDS pathogenesis and may contribute to further research focusing on the investigation of potential therapeutic targets for HIV-1. Human immunodeficiency virus type I (HIV-1) encodes a highly conserved trans-activator (Tat) protein, which is essential for viral replication and disease progression (1). Although Tat is a potent trans-activator in HIV-1 replication, HIV-1-mediated disease progression lasts for decades after primary infection (2). Host restriction mechanism...

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confidence: 99%

p53-Derived Host Restriction of HIV-1 Replication by Protein Kinase R-Mediated Tat Phosphorylation and Inactivation

Yoon

Kim

Byeon

et al. 2015

J Virol

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“…Among other factors, PIM-1 is directly linked to NF-B, as well as to cyclin dependent kinase 2 (CDK2). CDK2 has recently been demonstrated to be important for HIV-1 transcription by regulating the phosphorylation of HIV-1 Tat and CDK9 (28)(29)(30). The direct functional proximity of PIM-1 on the PIN to these factors can be viewed as a descriptor of the importance of PIM-1 in the context of HIV-1 latency.…”

Section: Kinome Profiling Reveals Pim-1 As a Kinase Involved In Latenmentioning

confidence: 99%

Kinase Control of Latent HIV-1 Infection: PIM-1 Kinase as a Major Contributor to HIV-1 Reactivation

Duverger

Wolschendorf

Anderson

et al. 2014

J Virol

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“…Induction of p21 (CIP1/ WAF1) expression by iron chelators was recently shown to inhibit CDK2 activity in 293T cells (17)(18)(19). Moreover, blocking of p21-mediated CDK9 and viral reverse transcriptase activities provides a potential protection barrier against HIV-1 infection (17).…”

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confidence: 99%

Phenyl-1-Pyridin-2yl-Ethanone-Based Iron Chelators Increase IκB-α Expression, Modulate CDK2 and CDK9 Activities, and Inhibit HIV-1 Transcription

Kumari

Iordanskiy

Kovalskyy

et al. 2014

Antimicrob Agents Chemother

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dHIV-1 transcription is activated by the Tat protein, which recruits CDK9/cyclin T1 to the HIV-1 promoter. CDK9 is phosphorylated by CDK2, which facilitates formation of the high-molecular-weight positive transcription elongation factor b (P-TEFb) complex. We previously showed that chelation of intracellular iron inhibits CDK2 and CDK9 activities and suppresses HIV-1 transcription, but the mechanism of the inhibition was not understood. In the present study, we tested a set of novel iron chelators for the ability to inhibit HIV-1 transcription and elucidated their mechanism of action. Novel phenyl-1-pyridin-2yl-ethanone (

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Phosphorylation of HIV-1 Tat by CDK2 in HIV-1 transcription

Cited by 82 publications

References 54 publications

p53-Derived Host Restriction of HIV-1 Replication by Protein Kinase R-Mediated Tat Phosphorylation and Inactivation

p53-Derived Host Restriction of HIV-1 Replication by Protein Kinase R-Mediated Tat Phosphorylation and Inactivation

Kinase Control of Latent HIV-1 Infection: PIM-1 Kinase as a Major Contributor to HIV-1 Reactivation

Phenyl-1-Pyridin-2yl-Ethanone-Based Iron Chelators Increase IκB-α Expression, Modulate CDK2 and CDK9 Activities, and Inhibit HIV-1 Transcription

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