Protein Kinase A Phosphorylation Activates Vpr-Induced Cell Cycle Arrest during Human Immunodeficiency Virus Type 1 Infection

Barnitz, R. Anthony; Wan, Fengyi; Tripuraneni, Vinay; Bolton, Diane L.; Lenardo, Michael J.

doi:10.1128/jvi.02273-09

Cited by 30 publications

(41 citation statements)

References 88 publications

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“…Nitrocellulose membranes were blocked in 5% nonfat milk in 0.1% PBS-Tween 20 (PBS-T) and probed with appropriate antibodies. Immunoblotting of phosphorylated proteins was carried out as described previously (17,32). Briefly, the gels were transferred to methanol-treated polyvinylidene fluoride membranes, retreated with methanol, and dried for 30 min.…”

Section: Methodsmentioning

confidence: 99%

Identification of an N-terminal Truncation of the NF-κB p65 Subunit That Specifically Modulates Ribosomal Protein S3-dependent NF-κB Gene Expression

Wier

Neighoff

Sun

et al. 2012

Journal of Biological Chemistry

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Background: RPS3 is an essential component that confers transcriptional specificity to NF-B. Results: A 21-186 truncation of p65 prevents NF-B activation-induced nuclear translocation of RPS3 by competing it off full-length p65. Conclusion:The 21-186 truncation of p65 selectively blocks RPS3-dependent NF-B gene transcription. Significance: These findings uncover a new function for the N-terminal domain of p65 and provide a novel strategy for selective inhibition of NF-B.

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Section: Methodsmentioning

confidence: 99%

Identification of an N-terminal Truncation of the NF-κB p65 Subunit That Specifically Modulates Ribosomal Protein S3-dependent NF-κB Gene Expression

Wier

Neighoff

Sun

et al. 2012

Journal of Biological Chemistry

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“…phorylation of the HIV-1 accessory proteins Nef and viral protein R is necessary for HIV-1 pathology (63,64). An approach targeting the cAMP-type I PKA pathway could, therefore, have several advantages in HIV infection, preserving innate and adaptative immune responses on the one hand, and directly limiting infectivity on the other hand.…”

Section: Discussionmentioning

confidence: 99%

Mice with Disrupted Type I Protein Kinase A Anchoring in T Cells Resist Retrovirus-Induced Immunodeficiency

Mosenden

Singh

Cornez

et al. 2011

The Journal of Immunology

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Type I protein kinase A (PKA) is targeted to the TCR-proximal signaling machinery by the A-kinase anchoring protein ezrin and negatively regulates T cell immune function through activation of the C-terminal Src kinase. RI anchoring disruptor (RIAD) is a high-affinity competitor peptide that specifically displaces type I PKA from A-kinase anchoring proteins. In this study, we disrupted type I PKA anchoring in peripheral T cells by expressing a soluble ezrin fragment with RIAD inserted in place of the endogenous A-kinase binding domain under the lck distal promoter in mice. Peripheral T cells from mice expressing the RIAD fusion protein (RIAD-transgenic mice) displayed augmented basal and TCR-activated signaling, enhanced T cell responsiveness assessed as IL-2 secretion, and reduced sensitivity to PGE2- and cAMP-mediated inhibition of T cell function. Hyperactivation of the cAMP–type I PKA pathway is involved in the T cell dysfunction of HIV infection, as well as murine AIDS, a disease model induced by infection of C57BL/6 mice with LP-BM5, a mixture of attenuated murine leukemia viruses. LP-BM5–infected RIAD-transgenic mice resist progression of murine AIDS and have improved viral control. This underscores the cAMP–type I PKA pathway in T cells as a putative target for therapeutic intervention in immunodeficiency diseases.

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“…In addition, Vpr is also found phosphorylated in mature virions [73]. The Ser79 phosphorylation has also been reported to be responsible for inducting G2 arrest [71]; an observation that was recently validated [74]. Notably, Ser79 of Vpr is a highly conserved amino acid among all HIV-1 and SIV isolates.…”

Section: Hiv-1 Proteins Involved In Nuclear Import Of the Pre-integramentioning

confidence: 91%

“…Notably, the replication defect was shown to be due to an inefficient nuclear import of viral nucleic acids as demonstrated by PCR analysis of the 2-LTR circles [72]. Recently, PKA (protein kinase A) was identified as the protein kinase involved in Ser79 specific Vpr phosphorylation [74]. The same study proved that specific phosphorylation of Vpr-Ser79 could be inhibited by PKA inactivation, which in turn impaired virion associated Vpr induced cell-cycle arrest in G2.…”

Section: Hiv-1 Proteins Involved In Nuclear Import Of the Pre-integramentioning

confidence: 93%

Role of Phosphorylation in the Nuclear Biology of HIV-1

Francis

Primio²,

Allouch³

et al. 2011

CMC

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The central events of HIV-1 life cycle occur at the nuclear level where the viral genome is integrated into the host cellular DNA in order to be expressed and replicated. The viral pre-integration complexes (PICs) are actively transported in the nuclear compartment where integration occurs in specific regions of the cellular chromatin. Similar to all viruses, HIV-1 encodes for a limited number of proteins that are insufficient to produce new viral progenies. Several cellular pathways are thus hijacked by HIV-1 to efficiently complete the replication cycle. The majority of viral proteins are substrates for cellular kinases indicating a pivotal role of these cellular enzymes at multiple steps of the HIV-1 life cycle. The nuclear biology of the cell is highly controlled by kinases (nuclear transport, DNA replication, repair and transcription) and many of these kinases also sustain the viral nuclear events. This review summarizes our current knowledge on kinases that are involved in HIV-1 replication cycle at the nuclear level, both directly through their catalytic activity on viral proteins and indirectly being activated by the virus. Among viral proteins directly modified by kinases is integrase (IN) the factor that catalyzes the integration of HIV-1 in the cellular genome. Notably, this recent discovery may shed light onto mechanisms underlying the different susceptibility of the main cell types targeted by HIV-1 (CD-4+ T-cell) depending on their activation status. Alternatively, kinases may act indirectly such as in the case of DNA repair factors activated following HIV-1 infection and demonstrated to regulate the viral life cycle. Finally, inhibition of cellular kinases interacting with HIV-1 at the nuclear level has been shown to severely affect the viral replication cycle, thus suggesting potential new therapeutic approaches.

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Protein Kinase A Phosphorylation Activates Vpr-Induced Cell Cycle Arrest during Human Immunodeficiency Virus Type 1 Infection

Cited by 30 publications

References 88 publications

Identification of an N-terminal Truncation of the NF-κB p65 Subunit That Specifically Modulates Ribosomal Protein S3-dependent NF-κB Gene Expression

Identification of an N-terminal Truncation of the NF-κB p65 Subunit That Specifically Modulates Ribosomal Protein S3-dependent NF-κB Gene Expression

Mice with Disrupted Type I Protein Kinase A Anchoring in T Cells Resist Retrovirus-Induced Immunodeficiency

Role of Phosphorylation in the Nuclear Biology of HIV-1

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