title: Nuclear PKC-θ facilitates rapid transcriptional responses in human memory CD4+ T cells through p65 and H2B phosphorylation.
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.
authors.affiliation: Faculty of Education, Science, Technology & Mathematics, University of Canberra, Canberra, Australian Capital Territory 2617, Australia Department of Microbiology & Immunology, The Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Li
authors.affiliation: Faculty of Education, Science, Technology & Mathematics, University of Canberra, Canberra, Australian Capital Territory 2617, Australia.
authors.forename: Kristine
authors.initials: K
authors.lastname: Hardy
authors.affiliation: The Kirby Institute, UNSW Australia, Sydney, New South Wales 2052, Australia.
authors.forename: Chan
authors.initials: C
authors.lastname: Phetsouphanh
authors.affiliation: Faculty of Education, Science, Technology & Mathematics, University of Canberra, Canberra, Australian Capital Territory 2617, Australia.
authors.forename: Wen Juan
authors.initials: WJ
authors.lastname: Tu
authors.affiliation: Faculty of Education, Science, Technology & Mathematics, University of Canberra, Canberra, Australian Capital Territory 2617, Australia.
authors.forename: Elissa L
authors.initials: EL
authors.lastname: Sutcliffe
authors.affiliation: Faculty of Education, Science, Technology & Mathematics, University of Canberra, Canberra, Australian Capital Territory 2617, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: McCuaig
authors.affiliation: Faculty of Education, Science, Technology & Mathematics, University of Canberra, Canberra, Australian Capital Territory 2617, Australia.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Sutton
authors.affiliation: Faculty of Education, Science, Technology & Mathematics, University of Canberra, Canberra, Australian Capital Territory 2617, Australia.
authors.forename: Anjum
authors.initials: A
authors.lastname: Zafar
authors.affiliation: The Kirby Institute, UNSW Australia, Sydney, New South Wales 2052, Australia.
authors.forename: C Mee Ling
authors.initials: CM
authors.lastname: Munier
authors.affiliation: The Kirby Institute, UNSW Australia, Sydney, New South Wales 2052, Australia.
authors.forename: John J
authors.initials: JJ
authors.lastname: Zaunders
authors.affiliation: The Kirby Institute, UNSW Australia, Sydney, New South Wales 2052, Australia.
authors.forename: Yin
authors.initials: Y
authors.lastname: Xu
authors.affiliation: The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 0200, Australia.
authors.forename: Angelo
authors.initials: A
authors.lastname: Theodoratos
authors.affiliation: Faculty of Education, Science, Technology & Mathematics, University of Canberra, Canberra, Australian Capital Territory 2617, Australia.
authors.forename: Abel
authors.initials: A
authors.lastname: Tan
authors.affiliation: Faculty of Education, Science, Technology & Mathematics, University of Canberra, Canberra, Australian Capital Territory 2617, Australia.
authors.forename: Pek Siew
authors.initials: PS
authors.lastname: Lim
authors.affiliation: JPT Peptide Technologies Gmbh, Berlin 12489, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Knaute
authors.affiliation: Department of Enzymology, Institute of Biochemistry & Biotechnology, Martin-Luther-University Halle-Wittenberg, Halle 06108, Germany.
authors.forename: Antonia
authors.initials: A
authors.lastname: Masch
authors.affiliation: JPT Peptide Technologies Gmbh, Berlin 12489, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zerweck
authors.affiliation: INSERM U955 Eq16 Faculte de medicine Henri Mondor and Universite Paris-Est Creteil/Vaccine Research Institute, Creteil 94010, France.
authors.forename: Vedran
authors.initials: V
authors.lastname: Brezar
authors.affiliation: The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 0200, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Milburn
authors.affiliation: Faculty of Education, Science, Technology & Mathematics, University of Canberra, Canberra, Australian Capital Territory 2617, Australia.
authors.forename: Jenny
authors.initials: J
authors.lastname: Dunn
authors.affiliation: The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 0200, Australia.
authors.forename: Marco G
authors.initials: MG
authors.lastname: Casarotto
authors.affiliation: Department of Microbiology & Immunology, The Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Turner
authors.affiliation: INSERM U955 Eq16 Faculte de medicine Henri Mondor and Universite Paris-Est Creteil/Vaccine Research Institute, Creteil 94010, France.
authors.forename: Nabila
authors.initials: N
authors.lastname: Seddiki
authors.affiliation: The Kirby Institute, UNSW Australia, Sydney, New South Wales 2052, Australia.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Kelleher
authors.affiliation: Faculty of Education, Science, Technology & Mathematics, University of Canberra, Canberra, Australian Capital Territory 2617, Australia sudha.rao@canberra.edu.au.
authors.forename: Sudha
authors.identifier: 0000-0001-9547-947X
authors.initials: S
authors.lastname: Rao
mesh_terms: D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002467:Cell Nucleus / Q000201:enzymology*; D002843:Chromatin / Q000378:metabolism; D005786:Gene Expression Regulation; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics*; D007527:Isoenzymes / Q000378:metabolism*; D019169:Jurkat Cells; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D006657:Histones; D007527:Isoenzymes; C498143:RELA protein, human; D051996:Transcription Factor RelA; D010768:Phosphoserine; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta
keywords: Chromatin; Memory; PKC-θ; T-cells; Transcription