Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Proc Natl Acad Sci U S A. 2024 May 28;121(22):e2314619121. doi: 10.1073/pnas.2314619121. Epub 2024 May 22.
Humoral immunity depends on the germinal center (GC) reaction where B cells are tightly controlled for class-switch recombination and somatic hypermutation and finally generated into plasma and memory B cells. However, how protein SUMOylation regulates the process of the GC reaction remains largely unknown. Here, we show that the expression of SUMO-specific protease 1 (SENP1) is up-regulated in GC B cells. Selective ablation of SENP1 in GC B cells results in impaired GC dark and light zone organization and reduced IgG1-switched GC B cells, leading to diminished production of class-switched antibodies with high-affinity in response to a TD antigen challenge. Mechanistically, SENP1 directly binds to Paired box protein 5 (PAX5) to mediate PAX5 deSUMOylation, sustaining PAX5 protein stability to promote the transcription of activation-induced cytidine deaminase. In summary, our study uncovers SUMOylation as an important posttranslational mechanism regulating GC B cell response.
体液免疫依赖于生发中心（GC）反应，其中 B 细胞受到严格控制以进行类别转换重组和体细胞超突变，最终生成浆细胞和记忆 B 细胞。然而，蛋白质 SUMO 化如何调节 GC 反应的过程在很大程度上仍是未知的。在这里，我们显示 SUMO 特异性蛋白酶 1（SENP1）的表达在 GC B 细胞中上调。GC B 细胞中 SENP1 的选择性缺失导致 GC 暗区和亮区组织受损，以及 IgG1 转换的 GC B 细胞减少，导致针对 TD 抗原挑战的高亲和力类别转换抗体的产生减少。在机制上，SENP1 直接与配对盒蛋白 5（PAX5）结合以介导 PAX5 的去 SUMO 化，维持 PAX5 蛋白稳定性以促进激活诱导的胞苷脱氨酶的转录。总之，我们的研究揭示了 SUMO 化作为调节 GC B 细胞反应的重要翻译后机制。
