The RNA-binding protein hnRNP F is required for the germinal center B cell response

• Published in: Nature communications Vol. 14; no. 1; p. 1731
• Main Authors: Huang, Hengjun, Li, Yuxing, Zhang, Gaopu, Ruan, Gui-Xin, Zhu, Zhijian, Chen, Wenjing, Zou, Jia, Zhang, Rui, Wang, Jing, Ouyang, Yu, Xu, Shengli, Ou, Xijun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.03.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 45/91; 631/250/1619/40; 631/250/2152/2153/1982; 631/250/2502; 631/337/1645/1792; 64/60; Affinity; Alternative splicing; Antibodies; Antibody response; Antigens; B-Lymphocytes; Base Sequence; c-Myc protein; CD40 antigen; Cell proliferation; Cell surface; Clonal deletion; Gene deletion; Gene regulation; Germinal Center - metabolism; Germinal centers; Heterogeneous-Nuclear Ribonucleoprotein Group A-B - metabolism; Heterogeneous-Nuclear Ribonucleoprotein Group F-H - metabolism; Heterogeneous-Nuclear Ribonucleoproteins - genetics; Heterogeneous-Nuclear Ribonucleoproteins - metabolism; Humanities and Social Sciences; Introns; Lymphocytes; Lymphocytes B; Lymphocytes T; multidisciplinary; Myc protein; Post-transcription; Proteins; Regulatory mechanisms (biology); Ribonucleic acid; RNA; RNA Precursors - genetics; RNA Precursors - metabolism; RNA-binding protein; Science; Science (multidisciplinary); Splicing
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-37308-z

The T cell-dependent (TD) antibody response involves the generation of high affinity, immunoglobulin heavy chain class-switched antibodies that are generated through germinal center (GC) response. This process is controlled by coordinated transcriptional and post-transcriptional gene regulatory mechanisms. RNA-binding proteins (RBPs) have emerged as critical players in post-transcriptional gene regulation. Here we demonstrate that B cell-specific deletion of RBP hnRNP F leads to diminished production of class-switched antibodies with high affinities in response to a TD antigen challenge. B cells deficient in hnRNP F are characterized by defective proliferation and c-Myc upregulation upon antigenic stimulation. Mechanistically, hnRNP F directly binds to the G-tracts of Cd40 pre-mRNA to promote the inclusion of Cd40 exon 6 that encodes its transmembrane domain, thus enabling appropriate CD40 cell surface expression. Furthermore, we find that hnRNP A1 and A2B1 can bind to the same region of Cd40 pre-mRNA but suppress exon 6 inclusion, suggesting that these hnRNPs and hnRNP F might antagonize each-other’s effects on Cd40 splicing. In summary, our study uncovers an important posttranscriptional mechanism regulating the GC response. The germinal centre (GC) response is characterized by regulated production of high affinity, class-switched antibodies in response to T-cell dependent antigens. Here authors show that the GC response is not only regulated at the transcriptional and protein levels, but also by the RNA-binding protein hnRNP F via alternative splicing of the co-stimulatory molecule CD40.