The ATP-dependent RNA helicase UPF1 plays a crucial role in various mRNA degradation pathways, most importantly in nonsense-mediated mRNA decay (NMD). Here, we show that UPF1 is upregulated during the early stages of B cell development and is important for early B cell development in the bone marrow. B-cell-specific Upf1 deletion in mice severely impedes the early to late LPre-B cell transition, in which V_H-D_HJ_H recombination occurs at the Igh gene. Furthermore, UPF1 is indispensable for V_H-D_HJ_H recombination, without affecting D_H-J_H recombination. Intriguingly, the genetic pre-arrangement of the Igh gene rescues the differentiation defect in early LPre-B cells under Upf1 deficient conditions. However, differentiation is blocked again following Ig light chain recombination, leading to a failure in development into immature B cells. Notably, UPF1 interacts with and regulates the expression of genes involved in immune responses, cell cycle control, NMD, and the unfolded protein response in B cells. Collectively, our findings underscore the critical roles of UPF1 during the early LPre-B cell stage and beyond, thus orchestrating B cell development.

ATP 依赖性 RNA 解旋酶 UPF1 在各种 mRNA 降解途径中发挥着至关重要的作用，最重要的是在无义介导的 mRNA 降解 (NMD) 中。在这里，我们发现 UPF1 在 B 细胞发育的早期阶段上调，并且对于骨髓中的早期 B 细胞发育很重要。小鼠 B 细胞特异性Upf1缺失严重阻碍了早期到晚期 LPre-B 细胞的转变，其中 V _H -D _H J _H重组发生在Igh基因处。此外，UPF1对于V _H -D _H J _H重组是必不可少的，而不影响D _H -J _H重组。有趣的是， Igh基因的遗传预排列挽救了早期 LPre-B 细胞在Upf1缺陷条件下的分化缺陷。然而， Ig 轻链重组后分化再次受阻，导致无法发育成未成熟 B 细胞。值得注意的是，UPF1 与 B 细胞中参与免疫反应、细胞周期控制、NMD 和未折叠蛋白反应的基因相互作用并调节其表达。总的来说，我们的研究结果强调了 UPF1 在早期 LPre-B 细胞阶段及以后的关键作用，从而协调 B 细胞的发育。