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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE259217 | GEO | 2025/07/19

REPOSITORIES: GEO

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

Project description: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.

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

Project description: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.

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