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

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.

The ARID Family Transcription Factor Bright Is Required for both Hematopoietic Stem Cell and B Lineage Development

“…B-1b cells have been proposed to be the primary source of T cell-independent antibody production and long-term protection against S. pneumoniae (33,34). Consistent with this proposition and with our previous data obtained from PC-KLH-immunized DN Bright transgenic mice (39,48), Bright knockout mice exhibited reduced IgM responses to primary immunization with intact S. pneumoniae serotype RSA32 cell wall-associated PC (Fig. 6C, left panel).…”

“…Strong blocks to conventional (B-2) pro-and pre-B development were observed in Bright Ϫ/Ϫ bone marrow. Peripheral Bright Ϫ/Ϫ B cell subsets (e.g., transitional and marginal zone B cells [MZB]), in which Bright is most highly expressed in normal cells (39,48), were also significantly reduced (Fig. 5B).…”

“…B cell-specific, transgenic overexpression of Bright leads to partial blocks at both the late-pre-B and T1 immature stages, skewed marginal-zone (MZ) B cell development, increased natural IgM antibody production, and intrinsic autoimmunity (49). Transgenic dominant negative (DN) inhibition of Bright DNA binding results in reduced levels of IgM in serum and functional perturbation of IgM secretion by B-1 cells (39,48). A small pool of Bright cycles from the nucleus into plasma membrane lipid rafts, where it associates with Btk to dampen antigen receptor signaling (48).…”

“…Transgenic dominant negative (DN) inhibition of Bright DNA binding results in reduced levels of IgM in serum and functional perturbation of IgM secretion by B-1 cells (39,48). A small pool of Bright cycles from the nucleus into plasma membrane lipid rafts, where it associates with Btk to dampen antigen receptor signaling (48).…”

Core Fucosylation of IgG B Cell Receptor Is Required for Antigen Recognition and Antibody Production

“…Upon Ag engagement, the ITAMs become phosphorylated by the Src family kinase Lyn and provide a binding site for the SH2 domaincontaining kinase Syk, which triggers the signaling cascades (6,7). Previous biochemical studies provided evidence that one of the earliest events that accompanies the phosphorylation of the BCR by Lyn is the association of the BCR with detergent-insoluble, sphingolipid-and cholesterol-rich membrane microdomains that were defined as lipid rafts (8,9). Subsequently, the BCR rapidly delivers Ag to intracellular compartments where it is proteolytically cleaved, which results in clonal expansion and differentiation of Ag-specific B cells into plasma cells or memory B cells (5).…”