scholarly journals Protein Kinase D3 Is Essential for Prostratin-Activated Transcription of Integrated HIV-1 Provirus Promoter via NF-κB Signaling Pathway

2014 ◽  
Vol 2014 ◽  
pp. 1-11
Author(s):  
Huiping Wang ◽  
Xinxing Zhu ◽  
Ying Zhu ◽  
Jiangfang Liu ◽  
Xiangming Hu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Active Form ◽  
Transcription Activation ◽  
Activation Effect ◽  
Upstream Kinase ◽  
Latent Hiv ◽  
First Time ◽  
Hiv 1

Prostratin has been proposed as a promising reagent for eradicating the latent HIV-1 provirus by inducing HIV-1 transcription activation. The molecular mechanism of this activation, however, is far from clear. Here, we show that the protein kinase D3 (PKD3) is essential for prostratin-induced transcription activation of latent HIV-1 provirus. First, silencing PKD3, but not the other members of PKD family, blocked prostratin-induced transcription of HIV-1. Second, overexpressing the constitutively active form of PKD3, but not the wild-type or kinase-dead form of PKD3, augmented the expression of HIV-1. Consistent with this observation, we found that prostratin could trigger PKD3 activation by inducing the phosphorylation of its activation loop. In addition, we identified PKCεof the novel PKC subfamily as the upstream kinase for this phosphorylation. Finally, the activation effect of PKD3 on HIV-1 transcription was shown to depend on the presence ofκB element and the prostratin-induced activation of NF-κB, as indicated by the fact that silencing PKD3 blocked prostratin-induced NF-κB activation and NF-κB-dependent HIV-1 transcription. Therefore, for the first time, PKD3 is implicated in the transcription activation of latent HIV-1 provirus, and our results revealed a molecular mechanism of prostratin-induced HIV-1 transcription via PKCε/PKD3/NF-κB signaling pathway.

AMPK: A Key Sensor of Fuel and Energy Status in Skeletal Muscle

Physiology ◽  
2006 ◽  
Vol 21 (1) ◽  
pp. 48-60 ◽  
Author(s):  
D. Grahame Hardie ◽  
Kei Sakamoto
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Signaling Pathway ◽  
Recent Work ◽  
Metabolic Changes ◽  
Energy Status ◽  
Upstream Kinase ◽  
Amp Activated Protein Kinase

Contraction induces marked metabolic changes in muscle, and the AMP-activated protein kinase (AMPK) is a good candidate to explain these effects. Recent work using a muscle-specific knockout of the upstream kinase, LKB1, has confirmed that the LKB1→AMPK cascade is the signaling pathway responsible for many of these effects.

scholarly journals Interaction of the CC-Chemokine RANTES with Glycosaminoglycans Activates a p44/p42 Mitogen-Activated Protein Kinase-Dependent Signaling Pathway and Enhances Human Immunodeficiency Virus Type 1 Infectivity

2002 ◽  
Vol 76 (5) ◽  
pp. 2245-2254 ◽  
Author(s):  
Theresa Li-Yun Chang ◽  
Cynthia J. Gordon ◽  
Branka Roscic-Mrkic ◽  
Christine Power ◽  
Amanda E. I. Proudfoot ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protein Kinase ◽  
Cell Surface ◽  
Signaling Pathway ◽  
Human Immunodeficiency Virus Type ◽  
Mitogen Activated Protein Kinase ◽  
Immunodeficiency Virus ◽  
Mitogen Activated Protein ◽  
Hiv 1

ABSTRACT The interaction of the CC-chemokine RANTES with its cell surface receptors transduces multiple intracellular signals: low concentrations of RANTES (1 to 10 nM) stimulate G-protein-coupled receptor (GPCR) activity, and higher concentrations (1 μM) activate a phosphotyrosine kinase (PTK)-dependent pathway. Here, we show that the higher RANTES concentrations induce rapid tyrosine phosphorylation of multiple proteins. Several src-family kinases (Fyn, Hck, Src) are activated, as is the focal adhesion kinase p125 FAK and, eventually, members of the p44/p42 mitogen-activated protein kinase (MAPK) family. This PTK signaling pathway can be activated independently of known seven-transmembrane GPCRs for RANTES because it occurs in cells that lack any such RANTES receptors. Instead, activation of the PTK signaling pathway is dependent on the expression of glycosaminoglycans (GAGs) on the cell surface, in that it could not be activated by RANTES in GAG-deficient cells. We have previously demonstrated that RANTES can both enhance and inhibit infection of cells with human immunodeficiency virus type 1 (HIV-1). Here we show that activation of both PTK and MAPK is involved in the enhancement of HIV-1 infectivity caused by RANTES in cells that lack GPCRs for RANTES but which express GAGs.

scholarly journals Protein Kinase C: One Pathway towards the Eradication of Latent HIV-1 Reservoirs

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Lisa N. McKernan ◽  
David Momjian ◽  
Joseph Kulkosky
Keyword(s):  
Protein Kinase C ◽  
Side Effects ◽  
Protein Kinase ◽  
Effective Means ◽  
Human Trials ◽  
Kinase C ◽  
Latent Hiv ◽  
Viable Mechanism ◽  
Hiv 1

An effective means to eradicate latent reservoirs in HIV-1-infected individuals remains elusive. Attempts to purge these reservoirs were undertaken over a decade ago without success. The subsequent lapse in further clinical attempts since may have been justified as our knowledge of the mechanisms which underpin the latent state still evolves. Although additional novel molecular antagonists of HIV-1 latency have subsequently been reported, these candidate agents have not been tested in human trials for reservoir ablation. This review provides an overview of the protein kinase C (PKC) pathway which can be modulated by small molecular agents to induce the expression of latent HIV-1 from within infected reservoir cells. Some of these agents have been tested against select cancers with seemingly tolerable side effects. As such, modulation of the PKC pathway may yet be a viable mechanism toward HIV-1 reservoir eradication.

Activation of Latent HIV-1 Expression by Protein Kinase C Agonists. A Novel Therapeutic Approach to Eradicate HIV-1 Reservoirs

2011 ◽  
Vol 12 (3) ◽  
pp. 348-356 ◽  
Author(s):  
Gonzalo Sanchez-Duffhues ◽  
Minh Q. Vo ◽  
Moises Perez ◽  
Marco A. Calzado ◽  
Santiago Moreno ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Therapeutic Approach ◽  
Kinase C ◽  
Latent Hiv ◽  
Hiv 1 ◽  
Novel Therapeutic

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

2015 ◽  
Vol 89 (8) ◽  
pp. 4262-4280 ◽  
Author(s):  
Cheol-Hee Yoon ◽  
Sang-Yoon Kim ◽  
Se Eun Byeon ◽  
Yideul Jeong ◽  
Jinjoo Lee ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Molecular Mechanism ◽  
Ectopic Expression ◽  
The United States ◽  
Restriction Factor ◽  
Protein Kinase R ◽  
Host Restriction ◽  
Cyclin T1 ◽  
Host Restriction Factor ◽  
Hiv 1

ABSTRACTTumor 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-1trans-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 eIF2αCAcells. 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.

scholarly journals Gnidimacrin, a Potent Anti-HIV Diterpene, Can Eliminate Latent HIV-1 Ex Vivo by Activation of Protein Kinase C β

2015 ◽  
Vol 58 (21) ◽  
pp. 8638-8646 ◽  
Author(s):  
Weihong Lai ◽  
Li Huang ◽  
Lei Zhu ◽  
Guido Ferrari ◽  
Cliburn Chan ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Ex Vivo ◽  
Kinase C ◽  
Latent Hiv ◽  
Anti Hiv ◽  
Hiv 1

scholarly journals Carbon Monoxide Inhibits Porcine Reproductive and Respiratory Syndrome Virus Replication by the Cyclic GMP/Protein Kinase G and NF-κB Signaling Pathway

2016 ◽  
Vol 91 (1) ◽  
Author(s):  
Angke Zhang ◽  
Lijuan Zhao ◽  
Na Li ◽  
Hong Duan ◽  
Hongliang Liu ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Protein Kinase ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Cyclic Gmp ◽  
Control Measures ◽  
Protein Kinase G ◽  
Economic Losses ◽  
Respiratory Syndrome Virus ◽  
Heme Oxygenase 1

ABSTRACT Porcine reproductive and respiratory syndrome virus (PRRSV) causes significant economic losses to the pork industry worldwide each year. Our previous research demonstrated that heme oxygenase-1 (HO-1) can suppress PRRSV replication via an unknown molecular mechanism. In this study, inhibition of PRRSV replication was demonstrated to be mediated by carbon monoxide (CO), a downstream metabolite of HO-1. Using several approaches, we demonstrate that CO significantly inhibited PRRSV replication in both a PRRSV permissive cell line, MARC-145, and the predominant cell type targeted during in vivo PRRSV infection, porcine alveolar macrophages (PAMs). Our results showed that CO inhibited intercellular spread of PRRSV; however, it did not affect PRRSV entry into host cells. Furthermore, CO was found to suppress PRRSV replication via the activation of the cyclic GMP/protein kinase G (cGMP/PKG) signaling pathway. CO significantly inhibits PRRSV-induced NF-κB activation, a required step for PRRSV replication. Moreover, CO significantly reduced PRRSV-induced proinflammatory cytokine mRNA levels. In conclusion, the present study demonstrates that CO exerts its anti-PRRSV effect by activating the cellular cGMP/PKG signaling pathway and by negatively regulating cellular NF-κB signaling. These findings not only provide new insights into the molecular mechanism of HO-1 inhibition of PRRSV replication but also suggest potential new control measures for future PRRSV outbreaks. IMPORTANCE PRRSV causes great economic losses each year to the swine industry worldwide. Carbon monoxide (CO), a metabolite of HO-1, has been shown to have antimicrobial and antiviral activities in infected cells. Our previous research demonstrated that HO-1 can suppress PRRSV replication. Here we show that endogenous CO produced through HO-1 catalysis mediates the antiviral effect of HO-1. CO inhibits PRRSV replication by activating the cellular cGMP/PKG signaling pathway and by negatively regulating cellular NF-κB signaling. These findings not only provide new insights into the molecular mechanism of HO-1 inhibition of PRRSV replication but also suggest potential new control measures for future PRRSV outbreaks.

scholarly journals HMBA Enhances Prostratin-Induced Activation of Latent HIV-1 via Suppressing the Expression of Negative Feedback Regulator A20/TNFAIP3 in NF-κB Signaling

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Duchu Chen ◽  
Huiping Wang ◽  
Jude Juventus Aweya ◽  
Yanheng Chen ◽  
Meihua Chen ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Negative Feedback ◽  
Transcriptional Activation ◽  
Transcription Initiation ◽  
Nuclear Translocation ◽  
Cellular Target ◽  
Negative Feedback Circuit ◽  
Latent Hiv ◽  
Hiv 1 ◽  
Feedback Regulator

In the past decade, much emphasis has been put on the transcriptional activation of HIV-1, which is proposed as a promised strategy for eradicating latent HIV-1 provirus. Two drugs, prostratin and hexamethylene bisacetamide (HMBA), have shown potent effects as inducers for releasing HIV-1 latency when used alone or in combination, although their cellular target(s) are currently not well understood, especially under drug combination. Here, we have shown that HMBA and prostratin synergistically release HIV-1 latency via different mechanisms. While prostratin strongly stimulates HMBA-induced HIV-1 transcription via improved P-TEFb activation, HMBA is capable of boosting NF-κB-dependent transcription initiation by suppressing prostratin-induced expression of the deubiquitinase A20, a negative feedback regulator in the NF-κB signaling pathway. In addition, HMBA was able to increase prostratin-induced phosphorylation and degradation of NF-κB inhibitor IκBα, thereby enhancing and prolonging prostratin-induced nuclear translocation of NF-κB, a prerequisite for stimulation of transcription initiation. Thus, by blocking the negative feedback circuit, HMBA functions as a signaling enhancer of the NF-κB signaling pathway.

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