Signalling of the BCR is regulated by a lipid rafts-localised transcription factor, Bright.
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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.
Schmidt, C., Kim, D., Ippolito, G. C., Naqvi, H. R., Probst, L., Mathur, S., ... Tucker, P. W.
complete list of authors
Schmidt, Christian||Kim, Dongkyoon||Ippolito, Gregory C||Naqvi, Hassan R||Probst, Loren||Mathur, Shawn||Rosas-Acosta, German||Wilson, Van G||Oldham, Athenia L||Poenie, Martin||Webb, Carol F||Tucker, Philip W