Chen Pengda, Lin Lianghua, Lin Xinyong, Liao Kunyu, Qiang Jiali, Wang Zhizhang, Wu Jianfeng, Li Yang, Yang Liang, Yao Nan, Song Huilin, Hong Yazhen, Liu Wen-Hsien, Zhang Yaoyang, Chang Xing, Du Dan, Xiao Changchun
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China.
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
Nat Commun. 2025 Mar 25;16(1):2906. doi: 10.1038/s41467-025-58212-8.
Upon encountering antigens, B cells may undergo multiple differentiation paths, including becoming plasma cells and memory B cells. Although it is well-known that transcription factors govern gene expression programs underpinning these fate decisions in transcriptional level, the role of post-transcriptional regulators, with a focus on RNA-binding proteins, in the fate determination are lesser known. Here we find by RNA interactome capture-coupled CRISPR/Cas9 functional screening that the Csde1-Strap complex plays an important role in plasma cell differentiation. Mechanistically, the Csde1-Strap complex establishes the expression kinetics of Bach2, a key regulator of plasma cell differentiation. Bach2 expression is rapidly induced to promote B cell expansion and then decreased to initiate plasma cell differentiation. The Csde1-Strap interaction is critical for their binding to Bach2 mRNA to couple its decay with translation to restrain the magnitude and duration of Bach2 protein expression. In the absence of Csde1 or Strap, Bach2 translation is de-coupled from mRNA decay, leading to elevated and prolonged expression of Bach2 protein and impaired plasma cell differentiation. This study thus establishes the functional RBP landscape in B cells and illustrates the fundamental importance of controlling protein expression kinetics in cell fate determination.
遇到抗原后，B细胞可能会经历多种分化途径，包括成为浆细胞和记忆B细胞。虽然众所周知转录因子在转录水平上调控着支撑这些命运决定的基因表达程序，但转录后调节因子，尤其是RNA结合蛋白，在命运决定中的作用却鲜为人知。在这里，我们通过RNA相互作用组捕获与CRISPR/Cas9功能筛选发现，Csde1-Strap复合物在浆细胞分化中起重要作用。从机制上讲，Csde1-Strap复合物确定了Bach2的表达动力学，Bach2是浆细胞分化的关键调节因子。Bach2的表达被迅速诱导以促进B细胞扩增，然后下降以启动浆细胞分化。Csde1-Strap相互作用对于它们与Bach2 mRNA的结合至关重要，从而将其衰变与翻译偶联起来，以限制Bach2蛋白表达的幅度和持续时间。在没有Csde1或Strap的情况下，Bach2的翻译与mRNA衰变解偶联，导致Bach2蛋白表达升高和延长，浆细胞分化受损。因此，这项研究确定了B细胞中的功能性RBP图谱，并说明了在细胞命运决定中控制蛋白质表达动力学的根本重要性。
