UPF1 governs early B cell development through regulation of V(D)J recombination

The ATP-dependent RNA helicase UPF1 plays a crucial role in various mRNA degradation pathways, particularly nonsense-mediated mRNA decay (NMD). Here, we unveil a novel role of UPF1, showcasing its upregulation during the early stages of B cell development, a phenomenon that is integral to the promotion of early B cell differentiation in the bone marrow. B cell-specific Upf1 deletion in mice severely impeded early to late LPre-B cell transition when VH-DHJH recombination occurs at the Igh gene. Furthermore, UPF1 proved indispensable for VH-DHJH recombination without affecting DH-JH recombination. Intriguingly, the genetic pre-arrangement of the Igh gene managed to rescue the differentiation defect in early LPre-B cells under Upf1 deficiency. However, the differentiation ceased after the light chain recombination, leading to the failure to develop into immature B cells. Significantly, UPF1 was shown to interact with and govern the expression of genes linked to immune responses, cell cycle regulation, NMD, and unfolded protein response in B cells. Collectively, our data underscores the critical roles of UPF1 in VH-DHJH recombination at early LPre-B cell stage and enabling the gene expression transition from early Lpre- to sPre-B cell stage, thereby establishing proper B cell development.