Signalling of the BCR is regulated by a lipid rafts-localised transcription factor, Bright

EMBO J. 2009 Mar 18;28(6):711-24. doi: 10.1038/emboj.2009.20. Epub 2009 Feb 12.

Abstract

Regulation of BCR signalling strength is crucial for B-cell development and function. Bright is a B-cell-restricted factor that complexes with Bruton's tyrosine kinase (Btk) and its substrate, transcription initiation factor-I (TFII-I), to activate immunoglobulin heavy chain gene transcription in the nucleus. Here we show that a palmitoylated pool of Bright is diverted to lipid rafts of resting B cells where it associates with signalosome components. After BCR ligation, Bright transiently interacts with sumoylation enzymes, blocks calcium flux and phosphorylation of Btk and TFII-I and is then discharged from lipid rafts as a Sumo-I-modified form. The resulting lipid raft concentration of Bright contributes to the signalling threshold of B cells, as their sensitivity to BCR stimulation decreases as the levels of Bright increase. Bright regulates signalling independent of its role in IgH transcription, as shown by specific dominant-negative titration of rafts-specific forms. This study identifies a BCR tuning mechanism in lipid rafts that is regulated by differential post-translational modification of a transcription factor with implications for B-cell tolerance and autoimmunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Animals
  • Antigens / metabolism
  • B-Lymphocytes / enzymology
  • DNA-Binding Proteins
  • Humans
  • Immunoglobulin M / genetics
  • Immunoglobulin M / metabolism
  • Lipoylation
  • Lymphocyte Activation
  • Membrane Microdomains / enzymology
  • Membrane Microdomains / metabolism*
  • Mice
  • Mutation / genetics
  • Oncogenes
  • Phosphorylation
  • Protein Binding
  • Protein Transport
  • Protein-Tyrosine Kinases / metabolism
  • Receptors, Antigen, B-Cell / metabolism*
  • Signal Transduction*
  • Small Ubiquitin-Related Modifier Proteins / metabolism
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism*
  • Transcription Factors, TFII / metabolism
  • Transcription, Genetic

Substances

  • ARID3A protein, human
  • Antigens
  • Arid3a protein, mouse
  • DNA-Binding Proteins
  • Immunoglobulin M
  • Receptors, Antigen, B-Cell
  • Small Ubiquitin-Related Modifier Proteins
  • Trans-Activators
  • Transcription Factors
  • Transcription Factors, TFII
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • Btk protein, mouse