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

In children, hyper-IgM syndrome type 1 (HIGM1) is a type of severe antibody disorder, the pathogenesis of which remains unclear. The antibody diversity is partially determined by the alternative splicing (AS) in the germline, which is mainly regulated by RNA-binding proteins, including Breast cancer amplified sequence 2 (Bcas2). However, the effect of Bcas2 on AS and antibody production in activated B cells, the main immune cell type in the germline, remains unknown. To fill this gap, we created a conditional knockout (cKO, B cell-specific AID-Cre <i>Bcas2</i> <sup>fl/fl</sup>) mouse model and performed integrated mechanistic analysis on alternative splicing (AS) and CSR in B cells through the RNA-sequencing approach, cross-linking immunoprecipitation and sequencing (CLIP-seq) analysis, and interactome proteomics. The results demonstrate that <i>Bcas2-</i>cKO significantly decreased CSR in activated B cells without inhibiting the B cell development. Mechanistically, Bcas2 interacts with SRSF7 at a conservative circular domain, forming a complex to regulate the AS of genes involved in the post-switch transcription, thereby causing broad-spectrum changes in antibody production. Importantly, we identified GAAGAA as the binding motif of Bcas2 to RNAs and revealed its essential role in the regulation of Bcas2-dependent AS and CSR. In addition, we detected a mutation of at the 3'UTR of <i>Bcas2</i> gene in children with HIGM1 and observed similar patterns of AS events and CSR in the patient that were discovered in the <i>Bcas2-</i>cKO B cells. Combined, our study elucidates the mechanism by which Bcas2-mediated AS affects CSR, offering potential insights into the clinical implications of Bcas2 in HIGM1.

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Journal
Exploration
Published
2025-02-16
DOI
https://doi.org/10.1002/exp.70015
Citations
1
Primary Topic
T-cell and B-cell Immunology
Type
article
Field-Weighted Citation Impact
0.80

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

Xuepeng Li, Xiangfeng Tang, Yongting Luo, Ping Liu et al.
1 citations
Exploration
T-cell and B-cell Immunology
0.80
article

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

Xuepeng Li, Xiangfeng Tang, Yongting Luo, Ping Liu, Yifei Yu, Weihan Xiao, Changchang Cao, Dan Su, Chenxu Lu, Ziwei Yi, Xingwang Zhao, Libing Liu, Wenbiao Shi, Jiaqiang Huang, Longjie Sun, Juan Chen, Yu Chen, Yixuan Li, Ming Zhang, Ran Wang, Zheng Ding, Jiazeng Sun, Fazheng Ren, Siyuan Sun, Jing Zhan, Bing Fang, Rong Liu, Weiru Yu, Lei Li, Yumei Lei
article en
1 citations

Abstract

In children, hyper-IgM syndrome type 1 (HIGM1) is a type of severe antibody disorder, the pathogenesis of which remains unclear. The antibody diversity is partially determined by the alternative splicing (AS) in the germline, which is mainly regulated by RNA-binding proteins, including Breast cancer amplified sequence 2 (Bcas2). However, the effect of Bcas2 on AS and antibody production in activated B cells, the main immune cell type in the germline, remains unknown. To fill this gap, we created a conditional knockout (cKO, B cell-specific AID-Cre <i>Bcas2</i> <sup>fl/fl</sup>) mouse model and performed integrated mechanistic analysis on alternative splicing (AS) and CSR in B cells through the RNA-sequencing approach, cross-linking immunoprecipitation and sequencing (CLIP-seq) analysis, and interactome proteomics. The results demonstrate that <i>Bcas2-</i>cKO significantly decreased CSR in activated B cells without inhibiting the B cell development. Mechanistically, Bcas2 interacts with SRSF7 at a conservative circular domain, forming a complex to regulate the AS of genes involved in the post-switch transcription, thereby causing broad-spectrum changes in antibody production. Importantly, we identified GAAGAA as the binding motif of Bcas2 to RNAs and revealed its essential role in the regulation of Bcas2-dependent AS and CSR. In addition, we detected a mutation of at the 3'UTR of <i>Bcas2</i> gene in children with HIGM1 and observed similar patterns of AS events and CSR in the patient that were discovered in the <i>Bcas2-</i>cKO B cells. Combined, our study elucidates the mechanism by which Bcas2-mediated AS affects CSR, offering potential insights into the clinical implications of Bcas2 in HIGM1.

ExplorationVol. 5(3)
Beijing Technology and Business University (CN), Chinese Academy of Sciences (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Cornell University (US), Chinese PLA General Hospital (CN), Institute of Zoology (CN), China Agricultural University (CN), Bohai University (CN)
China Agricultural University, Natural Science Foundation of Beijing Municipality, Chinese Universities Scientific Fund, National Key Research and Development Program of China
Openalex Percentile: Top 31%
T-cell and B-cell Immunology
0.80
DOIOpen Access PDFOpenAlex
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