Disruption of the RAG2 zinc finger motif impairs protein stability and causes immunodeficiency
Disruption of the RAG2 zinc finger motif impairs protein stability and causes immunodeficiency
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DOI：
10.1002/eji.201545896
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发表时间：
2016-04
影响因子：
5.4
通讯作者：
Keren Xu;Haifeng Liu;Zhubing Shi;Guangrong Song;Xiaoyan Zhu;Yuzhang Jiang;Zhaocai Zhou;Xiaolong Liu
中科院分区：
文献类型：
--
作者：
Keren Xu;Haifeng Liu;Zhubing Shi;Guangrong Song;Xiaoyan Zhu;Yuzhang Jiang;Zhaocai Zhou;Xiaolong Liu
尽管RAG 2核心结构域是V（D）J重组所需的最小区域，但非核心区域在重组调控中也起重要作用，并且该区域的突变通常与严重联合免疫缺陷相关。一个完整的了解RAG 2的非核心区域的功能和其个别残基的潜在贡献尚未实现。在这里，我们表明，RAG 2的非核心区域内的锌指基序是必不可少的RAG 2蛋白的稳定性。RAG 2非核心区的锌指基序从斑马鱼到人类都是高度保守的。携带锌指突变（C478 Y）的敲入小鼠表现出V（D）J重组效率降低和由于RAG 2不稳定性导致的T/B-细胞发育严重受损。进一步的研究还揭示了锌指基序对于RAG 2稳定性的重要性。此外，携带RAG 2非核心区突变（N474 S）的小鼠（位于C478附近但不结合锌）在RAG 2稳定性或T/B-细胞发育方面均未表现出损害。总之，我们的研究结果有助于定义RAG 2锌指基序的关键功能，并提供深入了解该基序内的突变和免疫缺陷疾病之间的关系。
Although the RAG2 core domain is the minimal region required for V(D)J recombination, the noncore region also plays important roles in the regulation of recombination, and mutations in this region are often related to severe combined immunodeficiency. A complete understanding of the functions of the RAG2 noncore region and the potential contributions of its individual residues has not yet been achieved. Here, we show that the zinc finger motif within the noncore region of RAG2 is indispensable for maintaining the stability of the RAG2 protein. The zinc finger motif in the noncore region of RAG2 is highly conserved from zebrafish to humans. Knock‐in mice carrying a zinc finger mutation (C478Y) exhibit decreased V(D)J recombination efficiency and serious impairment in T/B‐cell development due to RAG2 instability. Further studies also reveal the importance of the zinc finger motif for RAG2 stability. Moreover, mice harboring a RAG2 noncore region mutation (N474S), which is located near C478 but is not zinc‐binding, exhibit no impairment in either RAG2 stability or T/B‐cell development. Taken together, our findings contribute to defining critical functions of the RAG2 zinc finger motif and provide insights into the relationships between the mutations within this motif and immunodeficiency diseases.