浙江大学张龙小组发现，AARS1和AARS2感知乳酸来调节cGAS作为全局的赖氨酸乳酸转移酶。相关论文于2024年9月25日在线发表在《自然》杂志上。

研究人员鉴定了丙氨酰tRNA合成酶AARS1和AARS2（AARS1/2）为细胞内的L-乳酸传感器，这些传感器是L-乳酸刺激赖氨酸乳酸化修饰所必需的。AARS1/2及其演化上保守的大肠杆菌同源蛋白AlaRS以微摩尔亲和力结合L-乳酸，并直接催化L-乳酸进行ATP依赖性的赖氨酸末端乳酸化反应。在L-乳酸的响应下，AARS2与环状GMP-AMP合成酶（cGAS）结合，介导其乳酸化修饰，从而在细胞和小鼠体内使其失活。

通过建立一种用于赖氨酸乳酸化的遗传密码扩展正交系统，研究人员证明了在cGAS氨基末端特定位点存在乳酸基团会破坏cGAS的液体相分离及其在体内外的DNA感知能力。乳酸化模拟敲入会抑制cGAS，而乳酸化抗性敲入则可保护小鼠免受由高水平L-乳酸诱导的先天免疫逃逸。MCT1阻断可抑制受压小鼠体内cGAS的乳酸化，恢复先天免疫监视，从而抵抗病毒复制。因此，AARS1/2是保守的细胞内L-乳酸传感器，且作为乳酸转移酶在细胞中发挥重要作用。此外，乳酸化这一化学反应过程可靶向并失活cGAS。

据了解，L-乳酸通过乳酸化修饰蛋白质，但这一过程的具体机制尚不清楚。

附：英文原文

Title: AARS1 and AARS2 sense l-lactate to regulate cGAS as global lysine lactyltransferases

Author: Li, Heyu, Liu, Chao, Li, Ran, Zhou, Lili, Ran, Yu, Yang, Qiqing, Huang, Huizhe, Lu, Huasong, Song, Hai, Yang, Bing, Ru, Heng, Lin, Shixian, Zhang, Long

Issue&Volume: 2024-09-25

Abstract: L-lactate modifies proteins through lactylation1, but how this process occurs is unclear. Here we identify the alanyl-tRNA synthetases AARS1 and AARS2 (AARS1/2) as intracellular L-lactate sensors required for L-lactate to stimulate the lysine lactylome in cells. AARS1/2 and the evolutionarily conserved Escherichia coli orthologue AlaRS bind to L-lactate with micromolar affinity and they directly catalyse L-lactate for ATP-dependent lactylation on the lysine acceptor end. In response to L-lactate, AARS2 associates with cyclic GMP–AMP synthase (cGAS) and mediates its lactylation and inactivation in cells and in mice. By establishing a genetic code expansion orthogonal system for lactyl-lysine incorporation, we demonstrate that the presence of a lactyl moiety at a specific cGAS amino-terminal site abolishes cGAS liquid-like phase separation and DNA sensing in vitro and in vivo. A lactyl mimetic knock-in inhibits cGAS, whereas a lactyl-resistant knock-in protects mice against innate immune evasion induced through high levels of L-lactate. MCT1 blockade inhibits cGAS lactylation in stressed mice and restores innate immune surveillance, which in turn antagonizes viral replication. Thus, AARS1/2 are conserved intracellular L-lactate sensors and have an essential role as lactyltransferases. Moreover, a chemical reaction process of lactylation targets and inactivates cGAS.

DOI: 10.1038/s41586-024-07992-y

Source: https://www.nature.com/articles/s41586-024-07992-y