Murine T-cell differentiation antigen CD8 is a direct substrate of protein kinase C

1990 ◽  
Vol 170 (1) ◽  
pp. 10-16
Author(s):  
Masatoshi Tagawa ◽  
Leslie C. Griffith
2012 ◽  
Vol 188 (11) ◽  
pp. 5337-5347 ◽  
Author(s):  
Jian Ma ◽  
Yan Ding ◽  
Xianfeng Fang ◽  
Ruiqing Wang ◽  
Zuoming Sun

2021 ◽  
Author(s):  
Uri Mbonye ◽  
Konstantin Leskov ◽  
Meenakshi Shukla ◽  
Saba Valadkhan ◽  
Jonathan Karn

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.


1994 ◽  
Vol 86 (2) ◽  
pp. 399-401 ◽  
Author(s):  
Mitsuhiro Matsuda ◽  
Yasuhiro Maeda ◽  
Chikashi Shirakawa ◽  
Satoshi Morita ◽  
Atsuko Koyama ◽  
...  

1990 ◽  
pp. 73-82
Author(s):  
Nicola Berry ◽  
Yasutomi Nishizuka

Sign in / Sign up

Export Citation Format

Share Document