2024年12月23日，《免疫》杂志在线发表了美国南加州大学Pinghui Feng研究组的最新成果。该研究显示，嘧啶合成酶CTP合成酶1通过去氨基化IRF3，抑制抗病毒干扰素的诱导。

据悉，代谢通常与增殖和生长一起进行讨论。然而，代谢酶在代谢之外的作用——例如在先天免疫反应中的作用——仍未得到充分探索。

通过一个聚焦的短发夹RNA（shRNA）介导的筛选，研究人员发现嘧啶合成速率限制酶CTP合成酶1（CTPS1），是干扰素诱导的负调节因子。机制上，CTPS1与干扰素调节因子3（IRF3）相互作用并去氨基化IRF3。在N85位的去氨基化，会损害IRF3与含有IRF3响应元件的启动子的结合，从而抑制干扰素（IFN）诱导。

通过使用CTPS1条件性敲除小鼠，和IRF3去氨基化或抗去氨基化的敲入小鼠，研究人员证明了CTPS1驱动的IRF3去氨基化，在体内限制了病毒感染反应中的IFN诱导。然而，在免疫激活过程中，CTPS1对IRF3的去氨基化，会受到糖原合成酶激酶3β（GSK3β）的抑制，从而促进IFN诱导。

该研究展示了CTPS1如何在，不依赖其在嘧啶合成中的作用的情况下，调节先天免疫，进而扩展了代谢酶在免疫调控中的功能谱。

附：英文原文

Title: Pyrimidine synthesis enzyme CTP synthetase 1 suppresses antiviral interferon induction by deamidating IRF3

Author: Youliang Rao, Chao Qin, Ali Can Savas, Qizhi Liu, Shu Feng, Guoli Hou, Taolin Xie, Pinghui Feng

Issue&Volume: 2024-12-23

Abstract: Metabolism is typically contextualized in conjunction with proliferation and growth. The roles of metabolic enzymes beyond metabolism—such as in innate immune responses—are underexplored. Using a focused short hairpin RNA (shRNA)-mediated screen, we identified CTP synthetase 1 (CTPS1), a rate-limiting enzyme of pyrimidine synthesis, as a negative regulator of interferon induction. Mechanistically, CTPS1 interacts with and deamidates interferon regulatory factor 3 (IRF3). Deamidation at N85 impairs IRF3 binding to promoters containing IRF3-responsive elements, thus muting interferon (IFN) induction. Employing CTPS1 conditional deletion and IRF3 deamidated or deamidation-resistant knockin mice, we demonstrated that CTPS1-driven IRF3 deamidation restricts IFN induction in response to viral infection in vivo. However, during immune activation, IRF3 deamidation by CTPS1 is inhibited by glycogen synthase kinase 3 beta (GSK3β) to promote IFN induction. This work demonstrates how CTPS1 tames innate immunity independent of its role in pyrimidine synthesis, thus expanding the functional repertoire of metabolic enzymes into immune regulation.

DOI: 10.1016/j.immuni.2024.11.020

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00535-1