AARS1和AARS2感知L-乳酸盐以调节cGAS作为全球溶氨酸乳酸转移酶
1Life Sciences Institute and State Key Laboratory of Transvascular Implantation Devices of the Second Affiliated Hospital of the Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
Nature
|September 25, 2024
概括
亚兰基-tRNA合成酶 (AARS1/2) 感知L-乳酸盐,作为乳基转移酶来修改蛋白质. 这种乳化会使cGAS失活,影响先天免疫和病毒复制.
科学领域:
- 生物化学
- 分子生物学
- 免疫学
背景情况:
- 已知L-乳酸盐通过乳化修饰蛋白质,但基本的分子机制仍然基本不明.
- 了解乳化所涉及的酶和途径对于破译其在细胞过程中的作用至关重要.
研究的目的:
- 确定负责L-乳酸中介蛋白质乳酸化的细胞内传感器和酶.
- 研究乳化对循环GMP-AMP合成酶 (cGAS) 途径和先天免疫的作用.
主要方法:
- 生物化学试验以确定阿兰tRNA合成酶的L-乳酸盐结合亲和力和催化活性 (AARS1/2).
- 细胞和体内实验使用遗传密码扩展系统和敲入模型来研究cGAS乳酸和功能.
- 在受压力的小鼠中使用MCT1阻断的抑制研究.
主要成果:
- AARS1和AARS2被确定为细胞内L-乳酸盐传感器和直接乳酸转移酶,催化了依赖ATP的氨酸残留物.
- 通过AARS2诱导cGAS的乳糖化导致其无活化,损害DNA感知和先天免疫反应.
- 在cGAS的基因改造以模仿或抵抗乳化调节其相分离和DNA感应能力在体外和体内.
- 在受压力的小鼠中,MCT1阻塞降低了cGAS乳化,恢复了先天免疫监测,并对抗病毒复制.
结论:
- AARS1/2是保存的细胞内L-乳酸盐传感器和必要的乳酸转移酶.
- 蛋白质乳化,特别是针对cGAS,是先天免疫的关键调节机制.
- 向乳化通路提供了一个潜在的策略来调节免疫反应和对抗病毒感染.
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