Nuclear PKC-θ facilitates rapid transcriptional responses in human memory CD4+ T cells through p65 and H2B phosphorylation

Jasmine Li, Kristine Hardy, Chan Phetsouphanh, Wen Juan Tu, Elissa L Sutcliffe, Robert McCuaig, Christopher R Sutton, Anjum Zafar, C Mee Ling Munier, John J Zaunders, Yin Xu, Angelo Theodoratos, Abel Tan, Pek Siew Lim, Tobias Knaute, Antonia Masch, Johannes Zerweck, Vedran Brezar, Peter J Milburn, Jenny DunnMarco G Casarotto, Stephen J Turner, Nabila Seddiki, Anthony D Kelleher, Sudha Rao

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Abstract

Memory T cells are characterized by their rapid transcriptional programs upon re-stimulation. This transcriptional memory response is facilitated by permissive chromatin, but exactly how the permissive epigenetic landscape in memory T cells integrates incoming stimulatory signals remains poorly understood. By genome-wide ChIP-sequencing ex vivo human CD4(+) T cells, here, we show that the signaling enzyme, protein kinase C theta (PKC-θ) directly relays stimulatory signals to chromatin by binding to transcriptional-memory-responsive genes to induce transcriptional activation. Flanked by permissive histone modifications, these PKC-enriched regions are significantly enriched with NF-κB motifs in ex vivo bulk and vaccinia-responsive human memory CD4(+) T cells. Within the nucleus, PKC-θ catalytic activity maintains the Ser536 phosphorylation on the p65 subunit of NF-κB (also known as RelA) and can directly influence chromatin accessibility at transcriptional memory genes by regulating H2B deposition through Ser32 phosphorylation. Furthermore, using a cytoplasm-restricted PKC-θ mutant, we highlight that chromatin-anchored PKC-θ integrates activating signals at the chromatin template to elicit transcriptional memory responses in human memory T cells.

Original languageEnglish
Pages (from-to)2448-2461
Number of pages14
JournalJournal of Cell Science
Volume129
Issue number12
DOIs
Publication statusPublished - 2016

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    Li, J., Hardy, K., Phetsouphanh, C., Tu, W. J., Sutcliffe, E. L., McCuaig, R., Sutton, C. R., Zafar, A., Munier, C. M. L., Zaunders, J. J., Xu, Y., Theodoratos, A., Tan, A., Lim, P. S., Knaute, T., Masch, A., Zerweck, J., Brezar, V., Milburn, P. J., ... Rao, S. (2016). Nuclear PKC-θ facilitates rapid transcriptional responses in human memory CD4+ T cells through p65 and H2B phosphorylation. Journal of Cell Science, 129(12), 2448-2461. https://doi.org/10.1242/jcs.181248