In activated B cells, activation-induced cytidine deaminase (AID) generates programmed DNA lesions required for antibody class switch recombination (CSR), which may also threaten genome integrity. AID dynamically shuttles between cytoplasm and nucleus, and the majority stays in the cytoplasm due to active nuclear export mediated by its C-terminal peptide. In immunodeficient-patient cells expressing mutant AID lacking its C-terminus, a catalytically active AID-delC protein accumulates in the nucleus but nevertheless fails to support CSR. To resolve this apparent paradox, we dissected the function of AID-delC proteins in the CSR process and found that they cannot efficiently target antibody genes. We demonstrate that AID-delC proteins form condensates both in vivo and in vitro, dependent on its N-terminus and on a surface arginine-rich patch. Co-expression of AID-delC and wild-type AID leads to an unbalanced nuclear AID-delC/AID ratio, with AID-delC proteins able to trap wild-type AID in condensates, resulting in a dominant-negative phenotype that could contribute to immunodeficiency. The co-condensation model of mutant and wild-type proteins could be an alternative explanation for the dominant-negative effect in genetic disorders.

中文翻译：

---

C-末端缺失诱导的缩合螯合剂从免疫缺陷中的 IgH 靶标中获得帮助。

在活化的 B 细胞中，活化诱导的胞苷脱氨酶 (AID) 会产生抗体类转换重组 (CSR) 所需的程序性 DNA 损伤，这也可能威胁基因组的完整性。AID 在细胞质和细胞核之间动态穿梭，并且由于其 C 末端肽介导的主动核输出，大部分留在细胞质中。在表达缺乏其 C 端的突变 AID 的免疫缺陷患者细胞中，一种催化活性的 AID-delC 蛋白在细胞核中积累，但仍不能支持 CSR。为了解决这个明显的悖论，我们剖析了 AID-delC 蛋白在 CSR 过程中的功能，发现它们不能有效地靶向抗体基因。我们证明 AID-delC 蛋白在体内和体外都形成缩合物，这取决于其 N 末端和富含精氨酸的表面贴片。AID-delC 和野生型 AID 的共表达导致核 AID-delC/AID 比率不平衡，AID-delC 蛋白能够将野生型 AID 捕获在凝聚物中，从而导致显性负表型，可能有助于免疫缺陷。突变型和野生型蛋白质的共缩合模型可能是遗传疾病中显性负效应的另一种解释。