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

Abstract

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.