Oxaloacetate sensing promotes innate immune antiviral defence against influenza virus infection

Metabolic pathways instructing the cellular fate and function, however, the exact roles of metabolites in host immune responses remain undefined. Using unbiased metabolomics and pharmacological inhibition analysis, we report natural metabolic intermediate, oxaloacetate (OAA) primes effective broad-spectrum innate immunity against viral infection. OAA serves as an immune signal, rather than alters the metabolic flux to prompt antiviral immunity. Malate dehydrogenase 1 (MDH1) senses OAA to undergo dimerization, thus functions as a scaffold to recruit transcription factor ETS2 for phosphorylation by kinase TAOK1 at serine 313. Phosphorylated ETS2 is involved in the transcriptional regulation of TANK-binding kinase 1 (TBK1). OAA deficiency caused by genetic ablation and enzymatic inhibition of the ATP-citrate lyase (ACLY) decreases the antiviral immune responses through MDH1-TAOK1-ETS2-TBK1 pathway in vivo, and makes mice more susceptible to lethal viral infection. Taken together, our findings delineate an OAA-initiated immunometabolic circuit that links metabolic pathway and antiviral immune responses.