Signalling of the BCR is regulated by a lipid rafts-localised transcription factor, Bright.
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
Christian
C
Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712, USA.
Kim
Dongkyoon
D
Ippolito
Gregory C
GC
Naqvi
Hassan R
HR
Probst
Loren
L
Mathur
Shawn
S
Rosas-Acosta
German
G
Wilson
Van G
VG
Oldham
Athenia L
AL
Poenie
Martin
M
Webb
Carol F
CF
Tucker
Philip W
PW
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000941:Antigens / Q000378:metabolism; D001402:B-Lymphocytes / Q000201:enzymology; D004268:DNA-Binding Proteins; D006801:Humans; D007075:Immunoglobulin M / Q000235:genetics / Q000378:metabolism; D054878:Lipoylation; D008213:Lymphocyte Activation; D021962:Membrane Microdomains / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics; D009857:Oncogenes; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D019473:Transcription Factors, TFII / Q000378:metabolism; D014158:Transcription, Genetic
C490798:ARID3A protein, human; D000941:Antigens; C097532:Arid3a protein, mouse; D004268:DNA-Binding Proteins; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; D025841:Small Ubiquitin-Related Modifier Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D019473:Transcription Factors, TFII; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse