Institut de Recherches Cliniques de Montréal, 110 av. des Pins Ouest, Montréal, QC, H2W 1R7, Canada.
Department of Biochemistry and molecular medicine, 2900 boul. Édouard-Montpetit, bureau D-360, Montréal, QC, H3T 1J4, Canada.
Nat Commun. 2019 Jan 3;10(1):22. doi: 10.1038/s41467-018-07884-6.
Mechanisms regulating B cell development, activation, education in the germinal center (GC) and differentiation, underpin the humoral immune response. Protein arginine methyltransferase 5 (Prmt5), which catalyzes most symmetric dimethyl arginine protein modifications, is overexpressed in B cell lymphomas but its function in normal B cells is poorly defined. Here we show that Prmt5 is necessary for antibody responses and has essential but distinct functions in all proliferative B cell stages in mice. Prmt5 is necessary for B cell development by preventing p53-dependent and p53-independent blocks in Pro-B and Pre-B cells, respectively. By contrast, Prmt5 protects, via p53-independent pathways, mature B cells from apoptosis during activation, promotes GC expansion, and counters plasma cell differentiation. Phenotypic and RNA-seq data indicate that Prmt5 regulates GC light zone B cell fate by regulating transcriptional programs, achieved in part by ensuring RNA splicing fidelity. Our results establish Prmt5 as an essential regulator of B cell biology.
调节 B 细胞发育、激活、生发中心（GC）中的教育以及分化的机制是体液免疫反应的基础。蛋白质精氨酸甲基转移酶 5（Prmt5）催化大多数对称二甲基精氨酸蛋白修饰，在 B 细胞淋巴瘤中过度表达，但在正常 B 细胞中的功能尚未明确。本文中，我们发现 Prmt5 对于抗体反应是必需的，并且在小鼠所有增殖 B 细胞阶段具有必需但不同的功能。Prmt5 通过分别防止 Pro-B 和 Pre-B 细胞中 p53 依赖性和 p53 非依赖性阻滞，从而促进 B 细胞发育。相比之下，Prmt5 通过 p53 非依赖性途径保护激活过程中的成熟 B 细胞免于凋亡，促进 GC 扩增，并对抗浆细胞分化。表型和 RNA-seq 数据表明，Prmt5 通过调节转录程序来调节 GC 亮区 B 细胞命运，部分是通过确保 RNA 剪接保真度来实现的。我们的研究结果确立了 Prmt5 作为 B 细胞生物学的必需调节剂。
