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. MAPK-mediated phosphorylation and SUMOylation modulate BCL11B transcriptional activity, switching it from a repressor in naïve 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 PKC-mediated phosphorylation of BCL11B Ser2 does not significantly impact on BCL11B SUMOylation but negatively regulates NuRD recruitment by dampening the interaction with 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 IL2 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.