Induction of activation-induced cytidine deaminase-targeting adaptor 14-3-3γ is mediated by NF-κB-dependent recruitment of CFP1 to the 5'-CpG-3'-rich 14-3-3γ promoter and is sustained by E2A

J Immunol. 2013 Aug 15;191(4):1895-906. doi: 10.4049/jimmunol.1300922. Epub 2013 Jul 12.


Class switch DNA recombination (CSR) crucially diversifies Ab biologic effector functions. 14-3-3γ specifically binds to the 5'-AGCT-3' repeats in the IgH locus switch (S) regions. By interacting directly with the C-terminal region of activation-induced cytidine deaminase (AID), 14-3-3γ targets this enzyme to S regions to mediate CSR. In this study, we showed that 14-3-3γ was expressed in germinal center B cells in vivo and induced in B cells by T-dependent and T-independent primary CSR-inducing stimuli in vitro in humans and mice. Induction of 14-3-3γ was rapid, peaking within 3 h of stimulation by LPSs, and sustained over the course of AID and CSR induction. It was dependent on recruitment of NF-κB to the 14-3-3γ gene promoter. The NF-κB recruitment enhanced the occupancy of the CpG island within the 14-3-3γ promoter by CFP1, a component of the COMPASS histone methyltransferase complex, and promoter-specific enrichment of histone 3 lysine 4 trimethylation (H3K4me3), which is indicative of open chromatin state and marks transcription-competent promoters. NF-κB also potentiated the binding of B cell lineage-specific factor E2A to an E-box motif located immediately downstream of the two closely-spaced transcription start sites for sustained 14-3-3γ expression and CSR induction. Thus, 14-3-3γ induction in CSR is enabled by the CFP1-mediated H3K4me3 enrichment in the promoter, dependent on NF-κB and sustained by E2A.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 14-3-3 Proteins / biosynthesis*
  • 14-3-3 Proteins / genetics
  • 3' Untranslated Regions / genetics
  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism*
  • Base Sequence
  • Basic Helix-Loop-Helix Transcription Factors / physiology*
  • Cells, Cultured
  • Conserved Sequence
  • CpG Islands / genetics*
  • Cytidine Deaminase / metabolism
  • DNA-Binding Proteins / physiology*
  • E-Box Elements / genetics
  • Germinal Center / metabolism
  • HEK293 Cells
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histones / metabolism
  • Humans
  • Immunoglobulin Class Switching / physiology*
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / pharmacology
  • Lymphocyte Cooperation
  • Methylation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • NF-kappa B / physiology*
  • Promoter Regions, Genetic / genetics*
  • Protein Processing, Post-Translational
  • Sequence Alignment
  • Sequence Homology, Nucleic Acid
  • Specific Pathogen-Free Organisms
  • Trans-Activators / physiology*
  • Transcription Initiation Site
  • Up-Regulation / genetics
  • Up-Regulation / immunology


  • 14-3-3 Proteins
  • 3' Untranslated Regions
  • Basic Helix-Loop-Helix Transcription Factors
  • CXXC1 protein, human
  • Cxxc1 protein, mouse
  • DNA-Binding Proteins
  • Histones
  • Lipopolysaccharides
  • NF-kappa B
  • TCF3 protein, human
  • Tcf3 protein, mouse
  • Trans-Activators
  • lipopolysaccharide, E coli O55-B5
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase