RNA编辑酶ADAR1在B细胞早期发育中的作用及机制研究

免疫系统是维持人体健康的重要屏障。B 细胞是一类重要的免疫细胞，由共同淋巴祖细胞分化而来。B 细胞从骨髓中开始发育，经历祖B细胞、前 B 细胞、未成熟 B 细胞等发育阶段，最后在脾脏中分化为滤泡B细胞和边缘区 B 细胞。当受到抗原刺激时，脾脏产生的生发中心结构会分化出浆细胞以分泌特异性抗体清除抗原。B 细胞的发育过程受到了多种转录因子的调控和转录后修饰的影响，其中就包括 A-I 编辑。A-I 编辑是由RNA编辑酶 ADAR1 完成的，用来帮助免疫系统区分“自我”与“非我”。A-I 编辑会影响 I 型干扰素的产生、免疫细胞的发育与活化及免疫检查点阻断治疗中肿瘤细胞的敏感性等生物学过程。有研究报道ADAR1 对早期B细胞的发育起着重要的调控作用，但具体的调控机制仍然不清楚。

为了探究 ADAR1 在早期 B 细胞发育中的作用机制，本研究利用CreloxP 条件性基因敲除系统，构建了在小鼠早期 B 细胞中特异性敲除Adar1基因的小鼠模型。分析敲除小鼠 B 细胞的发育表型，发现ADAR1 的敲除导致了小鼠骨髓和脾脏中 B 细胞比例和数量的明显减少，其中骨髓B细胞的发育被阻滞在祖 B 细胞的阶段，同时 ADAR1 的敲除还导致了早期B细胞凋亡水平的明显升高。以上结果说明 ADAR1 通过可能抑制细胞凋亡促进了祖 B 细胞的发育。

为了探究 ADAR1 两种变体在 B 细胞早期发育过程中的功能差异，本研究构建了在 ADAR1 敲除小鼠中分别敲入 p150 变体和p110 变体的转基因小鼠模型。发现敲入 ADAR1 p150 变体可以完全回补敲除小鼠早期B细胞的发育，而敲入 p110 变体则完全不能回补早期B 细胞的发育。说明p150 变体而非 p110 变体在 B 细胞的发育过程中起到了重要的调控作用。为了进一步探究 p150 发挥作用的方式，本研究构建了p150 不同功能域的突变体，分别是 Z-DNA/RNA 结合功能突变体，RNA 编辑活性突变体以及双链 RNA 结合功能 突变体。 对这些 突变体进 行体内外功能实验，发现p150 双链 RNA 结合功能丧失后无法促进 B 细胞正常发育，而RNA编辑活性突变或者 Z-DNA/RNA 结合活性突变后仍然可以促进B 细胞的正常发育。以上结果说明 ADAR1 p150 变体通过双链 RNA 结合活性来促进早期B 细胞的发育。

本研究进一步对 ADAR1 调控 B 细胞早期发育的机制进行了探究，发现 ADAR1 通过 MDA5 依赖性和非依赖性途径发挥调控作用。敲除MDA5可以部分回补敲除小鼠早期 B 细胞的发育和凋亡表型，说明ADAR1 通过抑制 MDA5 的激活促进了早期祖 B 细胞的存活及其向后期的发育。敲除ADAR1 还导致了 pre-BCR 信号的异常激活及其表达的下降，在敲除小鼠中高表达外源 BCR 的同时敲除 MDA5 可以进一步回补敲除小鼠B细胞的发育表型。此外，已知的 PKR 和 OAS/RNase L 通路对ADAR1 调控早期B 细胞的发育并未发挥明显的调控作用。未来本研究将对ADAR1 结合的RNA 底物以及 ADAR1 调控 pre-BCR 表达的分子机制进行深入研究。

综上，本研究发现 ADAR1 是调控小鼠早期 B 细胞发育过程中的关键因子，调控了祖 B 细胞向前 B 细胞的发育过程，这种调控依赖于ADAR1p150 变体的双链 RNA 结合活性。本研究提出了 ADAR1 通过抑制MDA5通路激活及促进 pre-BCR 的表达共同控制了早期B 细胞发育的机制，为RNA 编辑酶调控 B 细胞发育研究提供了新的理论基础。

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