The RNA Binding Protein Bcas2 is Required for Antibody Class Switch in Activated-B Cells

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Hyper-IgM syndrome type 1 (HIGM1) is a severe antibody disorder in children with unclear pathogenesis.
• Alternative splicing (AS), regulated by RNA-binding proteins like Breast cancer amplified sequence 2 (Bcas2), influences antibody diversity.
• The role of Bcas2 in B cell alternative splicing and antibody production is largely unknown.

Purpose of the Study:

• To investigate the function of Bcas2 in B cell alternative splicing (AS) and its impact on immunoglobulin class switch recombination (CSR).
• To elucidate the molecular mechanisms underlying Bcas2-mediated AS and CSR.
• To explore the potential clinical relevance of Bcas2 in hyper-IgM syndrome type 1 (HIGM1).

Main Methods:

• Generated a B cell-specific conditional knockout mouse model (Bcas2-cKO).
• Performed integrated analysis using RNA-sequencing, cross-linking immunoprecipitation and sequencing (CLIP-seq), and interactome proteomics.
• Identified Bcas2 RNA binding motif and interacting partners.

Main Results:

• Bcas2 deficiency significantly reduced CSR in activated B cells without affecting B cell development.
• Bcas2 interacts with SRSF7 to regulate AS of genes involved in post-switch transcription.
• Identified GAAGAA as the Bcas2 RNA binding motif, crucial for Bcas2-dependent AS and CSR.
• Observed similar AS and CSR patterns in Bcas2-cKO B cells and HIGM1 patients with Bcas2 mutations.

Conclusions:

• Bcas2 plays a critical role in regulating alternative splicing and class switch recombination in B cells.
• Bcas2-mediated AS is a key mechanism affecting antibody production and is implicated in HIGM1 pathogenesis.
• Bcas2 is a potential therapeutic target for HIGM1 and related antibody disorders.