Japanese encephalitis virus orchestrates GLUT4-mediated glucose metabolism to potentiate viral replication via insulin receptor signaling

作者：Qi Wang, Ping Hao, Sheng-Yan Zhu, Jiang-fei Zhou, Sheng Feng, Qi Dai, Jian-chao Wei, Yun Young Go, Jing Chen, Bin Zhou · 发表于：PLoS Pathogens · 年份：2026 · DOI：10.1371/journal.ppat.1014164 · 被引用次数：1 · 研究领域：Mosquito-borne diseases and control、Infectious Encephalopathies and Encephalitis、HIV Research and Treatment

Flaviviruses intricately rewire host metabolic networks to establish a replication-permissive environment; however, the role of glucose transporter-mediated uptake, particularly via glucose transporter 4 (GLUT4), remains insufficiently defined. Japanese encephalitis virus (JEV) infection induces extensive remodeling of glucose metabolism, exemplified by the coordinated upregulation of critical metabolic effectors. Pharmacological blockade of glucose metabolic pathways markedly attenuates JEV replication, whereas exogenous glucose supplementation enhances viral propagation in a concentration-dependent manner. A targeted screen of 111 metabolism-oriented compounds identified selective GLUT4 inhibitors with potent antiviral efficacy. Notably, GLUT4 expression is consistently upregulated during JEV infection across multiple cell types, albeit to varying degrees, and is similarly induced by duck Tembusu virus (DTMUV), suggesting a potentially conserved mechanism shared by these two flaviviruses. However, broader validation across additional members of the Flavivirus genus remains warranted. Mechanistically, the viral nonstructural protein 3 (NS3) engages insulin receptor substrate 1 (IRS1), thereby activating the IRS1-PI3K-Akt-mTORC1-SREBP-1c signaling axis to transcriptionally drive GLUT4 expression. Concurrently, JEV infection induces PI3K-Akt-dependent phosphorylation of AS160, promoting GLUT4 vesicular trafficking via the coordinated action of Rab8 and Rab10. Collectively, the...