title: Phosphoproteomic analysis reveals an intrinsic pathway for the regulation of histone deacetylase 7 that controls the function of cytotoxic T lymphocytes.
abstract: Here we report an unbiased analysis of the cytotoxic T lymphocyte (CTL) serine-threonine phosphoproteome by high-resolution mass spectrometry. We identified approximately 2,000 phosphorylations in CTLs, of which approximately 450 were controlled by T cell antigen receptor (TCR) signaling. A significantly overrepresented group of molecules identified included transcription activators, corepressors and chromatin regulators. A focus on chromatin regulators showed that CTLs had high expression of the histone deacetylase HDAC7 but continually phosphorylated and exported this transcriptional repressor from the nucleus. Dephosphorylation of HDAC7 resulted in its accumulation in the nucleus and suppressed expression of genes encoding key cytokines, cytokine receptors and adhesion molecules that determine CTL function. Screening of the CTL phosphoproteome has thus identified intrinsic pathways of serine-threonine phosphorylation that target chromatin regulators and determine the CTL functional program.
authors.affiliation: The College of Life Sciences, Division of Immunology and Cell Biology, The University of Dundee, Dundee, Scotland, UK.
authors.forename: Maria N
authors.initials: MN
authors.lastname: Navarro
authors.forename: Jurgen
authors.initials: J
authors.lastname: Goebel
authors.forename: Carmen
authors.initials: C
authors.lastname: Feijoo-Carnero
authors.forename: Nick
authors.initials: N
authors.lastname: Morrice
authors.forename: Doreen A
authors.initials: DA
authors.lastname: Cantrell
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D003600:Cytosol / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D040901:Proteomics / Q000379:methods*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000378:metabolism*
chemical_list: D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D049452:Green Fluorescent Proteins; C543274:Hdac7 protein, mouse; D006655:Histone Deacetylases