Article
- The EMBO Journal (2009) 28, 711 - 724
- doi:10.1038/emboj.2009.20
Published online: 12 February 2009
Subject Categories:
Signalling of the BCR is regulated by a lipid rafts-localised transcription factor, Bright
Christian Schmidt1, Dongkyoon Kim1, Gregory C Ippolito1, Hassan R Naqvi2, Loren Probst1, Shawn Mathur1, German Rosas-Acosta3, Van G Wilson3, Athenia L Oldham4, Martin Poenie2, Carol F Webb4 and Philip W Tucker1
- Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX, USA
- Department of Molecular Cell and Developmental Biology, The University of Texas at Austin, Austin, TX, USA
- Department of Microbial and Molecular Pathogenesis, Texas A&M Health Science Center, College Station, TX, USA
- Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
Correspondence to:
Philip W Tucker, Institute for Cellular and Molecular Biology, Molecular Genetics and Microbiology, The University of Texas at Austin, 1 University Station A5000, Austin, TX 78712, USA. Tel.: +1 512 475 7705; Fax: +1 512 475 7707; E-mail: philtucker@mail.utexas.edu
Received 30 July 2008; Accepted 9 January 2009
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.
Keywords:
- B cell,
- immunity,
- signal transduction
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