scholarly journals Protein Kinase C and NF-κB–Dependent CD4 Downregulation in Macrophages Induced by T Cell-Derived Soluble Factors: Consequences for HIV-1 Infection

2011 ◽  
Vol 187 (2) ◽  
pp. 748-759 ◽  
Author(s):  
Rui André Saraiva Raposo ◽  
David C. Trudgian ◽  
Benjamin Thomas ◽  
Bonnie van Wilgenburg ◽  
Sally A. Cowley ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
T Cell ◽  
Protein Kinase ◽  
Soluble Factors ◽  
Kinase C ◽  
Hiv 1

scholarly journals Biogenesis of P-TEFb in CD4+ T cells to reverse HIV latency is mediated by protein kinase C (PKC)-independent signaling pathways

2021 ◽  
Author(s):  
Uri Mbonye ◽  
Konstantin Leskov ◽  
Meenakshi Shukla ◽  
Saba Valadkhan ◽  
Jonathan Karn
Keyword(s):  
T Cells ◽  
Protein Kinase C ◽  
T Cell ◽  
Protein Kinase ◽  
Signaling Pathways ◽  
Cd4 T Cells ◽  
Hiv Latency ◽  
Kinase C ◽  
Latent Hiv ◽  
Memory Cd4 T Cells

The switch between HIV latency and productive transcription is regulated by an auto-feedback mechanism initiated by the viral trans-activator Tat, which functions to recruit the host transcription elongation factor P-TEFb to proviral HIV. A heterodimeric complex of CDK9 and one of three cyclin T subunits, P-TEFb is expressed at vanishingly low levels in resting memory CD4 + T cells and cellular mechanisms controlling its availability are central to regulation of the emergence of HIV from latency. Using a well-characterized primary T-cell model of HIV latency alongside healthy donor memory CD4 + T cells, we characterized specific T-cell receptor (TCR) signaling pathways that regulate the generation of transcriptionally active P-TEFb, defined as the coordinate expression of cyclin T1 and phospho-Ser175 CDK9. Protein kinase C (PKC) agonists, such as ingenol and prostratin, stimulated active P-TEFb expression and reactivated latent HIV with minimal cytotoxicity, even in the absence of intracellular calcium mobilization with an ionophore. Unexpectedly, inhibition-based experiments demonstrated that PKC agonists and TCR-mobilized diacylglycerol signal through MAP kinases ERK1/2 rather than through PKC to effect the reactivation of both P-TEFb and latent HIV. Single-cell and bulk RNA-seq analyses revealed that of the four known isoforms of the Ras guanine nucleotide exchange factor RasGRP, RasGRP1 is by far the predominantly expressed diacylglycerol-dependent isoform in CD4 + T cells. RasGRP1 should therefore mediate the activation of ERK1/2 via Ras-Raf signaling upon TCR co-stimulation or PKC agonist challenge. Combined inhibition of the PI3K-mTORC2-AKT-mTORC1 pathway and the ERK1/2 activator MEK prior to TCR co-stimulation abrogated active P-TEFb expression and substantially suppressed latent HIV reactivation. Therefore, contrary to prevailing models, the coordinate reactivation of P-TEFb and latent HIV in primary T cells following either TCR co-stimulation or PKC agonist challenge is independent of PKC but rather involves two complementary signaling arms of the TCR cascade, namely, RasGRP1-Ras-Raf-MEK-ERK1/2 and PI3K-mTORC2-AKT-mTORC1.

Possible involvement of protein kinase C activation in down-regulation of CD3 antigen on adult T cell leukaemia cells

1994 ◽  
Vol 86 (2) ◽  
pp. 399-401 ◽  
Author(s):  
Mitsuhiro Matsuda ◽  
Yasuhiro Maeda ◽  
Chikashi Shirakawa ◽  
Satoshi Morita ◽  
Atsuko Koyama ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
T Cell ◽  
Protein Kinase ◽  
Cell Leukaemia ◽  
Down Regulation ◽  
Kinase C ◽  
Protein Kinase C Activation
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