Metabolic regulation of host defense against influenza virus infection through sensing oxaloacetate

Metabolic pathways determine cellular fate and function, however, the exact roles of metabolites in host immune responses against virus infection remain undefined. Here, we report that the metabolic pathways of oxaloacetate (OAA) are integrated with antiviral responses and OAA serves as a fundamental “cornerstone” to prime effective host resistance to the infection of influenza virus. MDH1 senses cellular OAA to undergo dimerization, thus functions as a scaffold to recruit the transcription factor ETS2 for phosphorylation by the kinase TAOK1 at serine 313. The phosphorylated ETS2 translocates into the nucleus and sustains the appropriate expression of TBK1 to provide broad-spectrum antiviral activity. OAA deficiency caused by ACLY genetic ablation decreases the antiviral immunity through MDH1–TAOK1–ETS2–TBK1 pathway in vivo, and makes mice more susceptible to lethal H1N1 virus infection. Our results uncover a previously unknown signaling pathway to maintain immune homeostasis by sensing cellular OAA, which links metabolism and antiviral innate immunity.