Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China.
Eur J Immunol. 2023 Dec;53(12):e2350536. doi: 10.1002/eji.202350536. Epub 2023 Sep 27.
Viral infections can result in metabolism rewiring of host cells, which in turn affects the viral lifecycle. Phosphoenolpyruvate (PEP), a metabolic intermediate in the glycolytic pathway, plays important roles in several biological processes including anti-tumor T cell immunity. However, whether PEP might participate in modulating viral infection remains largely unknown. Here, we demonstrate that PEP generally inhibits viral replication via upregulation of apoptosis-associated tyrosine kinase (AATK) expression. Targeted metabolomic analyses have shown that the intracellular level of PEP was increased upon viral infection. PEP treatment significantly restricted viral infection and hence declined subsequent inflammatory response both in vitro and in vivo. Besides, PEP took inhibitory effect on the stage of viral replication and also decreased the mortality of mice with viral infection. Mechanistically, PEP significantly promoted the expression of AATK. Knockdown of AATK led to enhanced viral replication and consequent increased levels of cytokines. Moreover, AATK deficiency disabled the antiviral effect of PEP. Together, our study reveals a previously unknown role of PEP in broadly inhibiting viral replication by promoting AATK expression, highlighting the potential application of activation or upregulation of the PEP-AATK axis in controlling viral infections.
病毒感染可导致宿主细胞的代谢重编程，进而影响病毒生命周期。磷酸烯醇丙酮酸（PEP）是糖酵解途径中的一种代谢中间产物，在包括抗肿瘤 T 细胞免疫在内的多种生物学过程中发挥重要作用。然而，PEP 是否可能参与调节病毒感染在很大程度上仍是未知的。本研究表明，PEP 通过上调凋亡相关酪氨酸激酶（AATK）的表达普遍抑制病毒复制。靶向代谢组学分析表明，病毒感染后细胞内 PEP 水平升高。PEP 处理在体外和体内均显著限制病毒感染，并降低随后的炎症反应。此外，PEP 对病毒复制阶段具有抑制作用，并降低了病毒感染小鼠的死亡率。在机制上，PEP 可显著促进 AATK 的表达。敲低 AATK 导致病毒复制增强，细胞因子水平升高。此外，AATK 缺陷使 PEP 的抗病毒作用失活。总之，本研究揭示了 PEP 通过促进 AATK 表达广泛抑制病毒复制的未知作用，突出了激活或上调 PEP-AATK 轴在控制病毒感染方面的潜在应用。
