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N 6 -methyladenosine RNA modification-mediated cellular metabolism rewiring inhibits viral replication.

Science 2019 August 23
Host cell metabolism can be modulated by viral infection, affecting viral survival or clearance. The cellular metabolism rewiring mediated by N 6 -methyladenosine (m6 A) modification in virus-host interaction remains largely unknown. Here we report that in response to viral infection, host cells impair the enzymatic activity of RNA m6 A demethylase ALKBH5. This increases the m6 A methylation on α-ketoglutarate dehydrogenase (OGDH) mRNA to reduce its mRNA stability and protein expression. Reduced OGDH decreases the production of metabolite itaconate that is required for viral replication. With reduced OGDH and itaconate production in vivo, ALKBH5-deficient mice display an innate immune response-independent resistance to viral challenge. Our findings reveal that m6 A RNA modification-mediated down-regulation of OGDH-Itaconate pathway reprograms cellular metabolism to inhibit viral replication, proposing potential targets for controlling viral infection.

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