Rao Youliang, Qin Chao, Savas Ali Can, Liu Qizhi, Feng Shu, Hou Guoli, Xie Taolin, Feng Pinghui
Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
Immunity. 2025 Jan 14;58(1):74-89.e6. doi: 10.1016/j.immuni.2024.11.020. Epub 2024 Dec 23.
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.
新陈代谢通常与增殖和生长相关联。代谢酶在新陈代谢之外的作用，如在先天免疫反应中的作用，尚未得到充分探索。通过聚焦短发夹RNA（shRNA）介导的筛选，我们鉴定出胞苷三磷酸合成酶1（CTPS1），一种嘧啶合成的限速酶，作为干扰素诱导的负调节因子。从机制上讲，CTPS1与干扰素调节因子3（IRF3）相互作用并使其脱酰胺。N85位点的脱酰胺作用会损害IRF3与含有IRF3反应元件的启动子的结合，从而抑制干扰素（IFN）的诱导。利用CTPS1条件性缺失以及IRF3脱酰胺或抗脱酰胺敲入小鼠，我们证明CTPS1驱动的IRF3脱酰胺在体内限制了对病毒感染的IFN诱导。然而，在免疫激活过程中，糖原合酶激酶3β（GSK3β）抑制CTPS1对IRF3的脱酰胺作用，以促进IFN诱导。这项工作展示了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，从而将代谢酶的功能范围扩展到免疫调节领域。
