The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA.
Cell Rep. 2021 Oct 12;37(2):109824. doi: 10.1016/j.celrep.2021.109824.
RAG1 and RAG2 form a tetramer nuclease to initiate V(D)J recombination in developing T and B lymphocytes. The RAG1 protein evolves from a transposon ancestor and possesses nuclease activity that requires interaction with RAG2. Here, we show that the human RAG1 aggregates in the nucleus in the absence of RAG2, exhibiting an extremely low V(D)J recombination activity. In contrast, RAG2 does not aggregate by itself, but it interacts with RAG1 to disrupt RAG1 aggregates and thereby activate robust V(D)J recombination. Moreover, RAG2 from mouse and zebrafish could not disrupt the aggregation of human RAG1 as efficiently as human RAG2 did, indicating a species-specific regulatory mechanism for RAG1 by RAG2. Therefore, we propose that RAG2 coevolves with RAG1 to release inert RAG1 from aggregates and thereby activate V(D)J recombination to generate diverse antigen receptors in lymphocytes.
RAG1 和 RAG2 形成四聚体核酸酶，在发育中的 T 和 B 淋巴细胞中启动 V(D)J 重组。RAG1 蛋白由转座子祖先进化而来，具有需要与 RAG2 相互作用的核酸酶活性。在这里，我们表明，在没有 RAG2 的情况下，人类 RAG1 在核内聚集，表现出极低的 V(D)J 重组活性。相比之下，RAG2 本身不会聚集，但它与 RAG1 相互作用，破坏 RAG1 聚集体，从而激活强大的 V(D)J 重组。此外，来自小鼠和斑马鱼的 RAG2 不能像人类 RAG2 那样有效地破坏人类 RAG1 的聚集，表明 RAG2 对 RAG1 的调控机制具有种属特异性。因此，我们提出 RAG2 与 RAG1 共同进化，将无活性的 RAG1 从聚集体中释放出来，从而激活 V(D)J 重组，在淋巴细胞中产生多样化的抗原受体。
