Laboratory of Genome Diversification and Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
Bioinformatics and Omics Data Science Technology Platform, Berlin Institute of Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
J Exp Med. 2020 Oct 5;217(10). doi: 10.1084/jem.20200137.
The establishment of protective humoral immunity is dependent on the ability of mature B cells to undergo antibody gene diversification while adjusting to the physiological stressors induced by activation with the antigen. Mature B cells diversify their antibody genes by class switch recombination (CSR) and somatic hypermutation (SHM), which are both dependent on efficient induction of activation-induced cytidine deaminase (AID). Here, we identified PDGFA-associated protein 1 (Pdap1) as an essential regulator of cellular homeostasis in mature B cells. Pdap1 deficiency leads to sustained expression of the integrated stress response (ISR) effector activating transcription factor 4 (Atf4) and induction of the ISR transcriptional program, increased cell death, and defective AID expression. As a consequence, loss of Pdap1 reduces germinal center B cell formation and impairs CSR and SHM. Thus, Pdap1 protects mature B cells against chronic ISR activation and ensures efficient antibody diversification by promoting their survival and optimal function.
保护性体液免疫的建立依赖于成熟 B 细胞在与抗原激活的同时，调整生理应激而发生抗体基因多样化的能力。成熟 B 细胞通过类别转换重组（CSR）和体细胞高频突变（SHM）使抗体基因多样化，这两者都依赖于有效诱导激活诱导胞嘧啶脱氨酶（AID）。在这里，我们鉴定出血小板衍生生长因子 A 相关蛋白 1（Pdap1）是成熟 B 细胞细胞内稳态的必需调节剂。Pdap1 缺陷导致持续表达整合应激反应（ISR）效应物激活转录因子 4（Atf4）和诱导 ISR 转录程序、细胞死亡增加以及 AID 表达缺陷。因此，Pdap1 减少生发中心 B 细胞的形成并损害 CSR 和 SHM。因此，Pdap1 通过促进成熟 B 细胞的存活和最佳功能来保护它们免受慢性 ISR 激活并确保有效的抗体多样化。
