title: Protein Kinase C-Mediated Phosphorylation of BCL11B at Serine 2 Negatively Regulates Its Interaction with NuRD Complexes during CD4+ T-Cell Activation.
abstract: The transcription factor BCL11B/CTIP2 is a major regulatory protein implicated in various aspects of development, function and survival of T cells. Mitogen-activated protein kinase (MAPK)-mediated phosphorylation and SUMOylation modulate BCL11B transcriptional activity, switching it from a repressor in naive murine thymocytes to a transcriptional activator in activated thymocytes. Here, we show that BCL11B interacts via its conserved N-terminal MSRRKQ motif with endogenous MTA1 and MTA3 proteins to recruit various NuRD complexes. Furthermore, we demonstrate that protein kinase C (PKC)-mediated phosphorylation of BCL11B Ser2 does not significantly impact BCL11B SUMOylation but negatively regulates NuRD recruitment by dampening the interaction with MTA1 or MTA3 (MTA1/3) and RbAp46 proteins. We detected increased phosphorylation of BCL11B Ser2 upon in vivo activation of transformed and primary human CD4(+) T cells. We show that following activation of CD4(+) T cells, BCL11B still binds to IL-2 and Id2 promoters but activates their transcription by recruiting P300 instead of MTA1. Prolonged stimulation results in the direct transcriptional repression of BCL11B by KLF4. Our results unveil Ser2 phosphorylation as a new BCL11B posttranslational modification linking PKC signaling pathway to T-cell receptor (TCR) activation and define a simple model for the functional switch of BCL11B from a transcriptional repressor to an activator during TCR activation of human CD4(+) T cells.
authors.affiliation: Université Lille, CNRS, Institut Pasteur de Lille, UMR 8161, Mechanisms of Tumorigenesis and Targeted Therapies (M3T), Lille, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Dubuissez
authors.affiliation: Université Lille, CNRS, Institut Pasteur de Lille, UMR 8161, Mechanisms of Tumorigenesis and Targeted Therapies (M3T), Lille, France.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Loison
authors.affiliation: Université Lille, CNRS, Institut Pasteur de Lille, UMR 8161, Mechanisms of Tumorigenesis and Targeted Therapies (M3T), Lille, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Paget
authors.affiliation: Université Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019, UMR8204, Center for Infection and Immunity of Lille (CIIL), Lille, France.
authors.forename: Han
authors.initials: H
authors.lastname: Vorng
authors.affiliation: Université Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019, UMR8204, Center for Infection and Immunity of Lille (CIIL), Lille, France.
authors.forename: Saliha
authors.initials: S
authors.lastname: Ait-Yahia
authors.affiliation: University of Strasbourg, IUT Louis Pasteur, EA7292, Dynamic of Host Pathogen Interactions, Institute of Parasitology and Tropical Pathology, Strasbourg, France Institut Universitaire de France, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Rohr
authors.affiliation: Université Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019, UMR8204, Center for Infection and Immunity of Lille (CIIL), Lille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Tsicopoulos
authors.affiliation: Université Lille, CNRS, Institut Pasteur de Lille, UMR 8161, Mechanisms of Tumorigenesis and Targeted Therapies (M3T), Lille, France dominique.leprince@ibl.cnrs.fr.
authors.forename: Dominique
authors.initials: D
authors.lastname: Leprince
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D000090062:Kruppel-Like Factor 4; D008213:Lymphocyte Activation; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D056524:Retinoblastoma-Binding Protein 7 / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: C479740:BCL11B protein, human; C508594:IL2 protein, human; D007376:Interleukin-2; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; C486657:MTA3 protein, human; C089320:MTA1 protein, human; D009363:Neoplasm Proteins; C490746:RBBP7 protein, human; D012097:Repressor Proteins; D056524:Retinoblastoma-Binding Protein 7; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D012694:Serine; D011493:Protein Kinase C; D006655:Histone Deacetylases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex