1. Signalling of the BCR is regulated by a lipid rafts-localised transcription factor, Bright
- Author
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Philip W. Tucker, Gregory C. Ippolito, Germán Rosas-Acosta, Dongkyoon Kim, Van G. Wilson, Athenia L. Oldham, Christian Schmidt, Loren Probst, Carol F. Webb, Hassan R Naqvi, Martin Poenie, and Shawn Mathur
- Subjects
Transcription, Genetic ,Lipoylation ,Receptors, Antigen, B-Cell ,Lymphocyte Activation ,DNA-binding protein ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,Transcription Factors, TFII ,Membrane Microdomains ,hemic and lymphatic diseases ,Calcium flux ,Agammaglobulinaemia Tyrosine Kinase ,Animals ,Humans ,Bruton's tyrosine kinase ,Antigens ,Phosphorylation ,Molecular Biology ,Lipid raft ,Transcription factor ,B-Lymphocytes ,General Immunology and Microbiology ,biology ,General Neuroscience ,breakpoint cluster region ,Oncogenes ,Protein-Tyrosine Kinases ,Molecular biology ,Cell biology ,DNA-Binding Proteins ,Protein Transport ,Immunoglobulin M ,Mutation ,Small Ubiquitin-Related Modifier Proteins ,Trans-Activators ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Tyrosine kinase ,Protein Binding ,Signal Transduction ,Transcription Factors - 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.
- Published
- 2009
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