HnRNP A1 and A2B1 enforce Ezh2 mRNA splicing to promote germinal center B cell responses

HnRNP A1 and A2B1 enforce Ezh2 mRNA splicing to promote germinal center B cell responses

Nature Communications

10.1038/s41467-026-74159-w

https://doi.org/10.1038/s41467-026-74159-w

Zhijian Zhu, Rui Zhang, Haoran Kang, Meiyuan Chen, Hengjun Huang, Jing Wang, Ling Guo, Yuxing Li, Wenjing Chen, Limin Meng, Ruisi Wang, Ling Li, Kong-Peng Lam, Shengli Xu, Xijun Ou

11 June 2026

Zhu, Z., Zhang, R., Kang, H., Chen, M., Huang, H., Wang, J., Guo, L., Li, Y., Chen, W., Meng, L., Wang, R., Li, L., Lam, K.-P., Xu, S., & Ou, X. (2026). HnRNP A1 and A2B1 enforce Ezh2 mRNA splicing to promote germinal center B cell responses. Nature Communications. https://doi.org/10.1038/s41467-026-74159-w

Heterogeneous nuclear ribonucleoproteins (hnRNP) are key regulators of gene expression, yet the physiological functions of the highly homologous hnRNP A1 and A2B1 in B cells remain unclear. Here, we conditionally delete Hnrnpa1 and Hnrnpa2b1 in mouse B cells and find that loss of hnRNP A1 and A2B1 compromises the germinal center (GC) reaction during T cell-dependent immune responses. Loss of hnRNP A1 and A2B1 impairs GC B cell proliferation and high-affinity antibody production. Mechanistically, hnRNP A1/A2B1 bind UAG-rich motifs in Ezh2 pre-mRNA to promote Ezh2 exon 14 inclusion, thereby preserving EZH2 catalytic activity; in their absence, Ezh2 exon 14-skipping produces a catalytically inactive EZH2 isoform (Ezh2Δ14) with diminished repression of the cell cycle inhibitor Cdkn1a. The resulting CDKN1A accumulation restricts B cell proliferation, while Cdkn1a deletion partially rescues the GC defects in B cells deficient for hnRNP A1 and A2B1. Our findings thus uncover an hnRNP A1/A2B1–EZH2–CDKN1A axis that integrates RNA splicing with epigenetic regulation of B cell immunity.

Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

This research is supported by core funding from: A*STAR Singapore Immunology Network (A*STAR SIgN)
Grant Reference no. : NA

https://oar.a-star.edu.sg/communities-collections/articles/23326

2041-1723

Singapore Immunology Network

https://doi.org/10.1038/s41467-026-74159-w