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

Christian Schmidt, Dongkyoon Kim, Gregory C. Ippolito, Hassan R. Naqvi, Loren Probst, Shawn Mathur, German Rosas-Acosta, Van G. Wilson, Athenia L. Oldham, Martin Poenie, Carol F. Webb, Philip W. Tucker

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)711-724
Number of pages14
JournalEMBO Journal
Volume28
Issue number6
DOIs
StatePublished - Mar 18 2009

Keywords

  • B cell
  • Immunity
  • Signal transduction

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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