TY - JOUR T1 - <em>N</em><sup>6</sup>-methyladenosine RNA modification–mediated cellular metabolism rewiring inhibits viral replication JF - Science JO - Science SP - 1171 LP - 1176 DO - 10.1126/science.aax4468 VL - 365 IS - 6458 AU - Liu, Yang AU - You, Yuling AU - Lu, Zhike AU - Yang, Jiang AU - Li, Panpan AU - Liu, Lun AU - Xu, Henan AU - Niu, Yamei AU - Cao, Xuetao Y1 - 2019/09/13 UR - http://science.sciencemag.org/content/365/6458/1171.abstract N2 - N6-methyladenosine (m6A) RNA modification regulates various cellular functions. Liu et al. found that host cells impair RNA m6A demethylase activity after viral infection, leading to increased m6A and reduced stability of α-ketoglutarate dehydrogenase (OGDH) mRNA. As a result, reduced OGDH decreases the generation of itaconate, thereby inhibiting viral replication. The authors explore the function of OGDH and itaconate in viral infection, provide insights into m6A RNA modification and metabolic reprogramming in modulating virus-host interaction, and suggest potential therapeutic targets for the control of viral infection.Science, this issue p. 1171Host cell metabolism can be modulated by viral infection, affecting viral survival or clearance. Yet the cellular metabolism rewiring mediated by the N6-methyladenosine (m6A) modification in interactions between virus and host remains largely unknown. Here we report that in response to viral infection, host cells impair the enzymatic activity of the RNA m6A demethylase ALKBH5. This behavior increases the m6A methylation on α-ketoglutarate dehydrogenase (OGDH) messenger RNA (mRNA) to reduce its mRNA stability and protein expression. Reduced OGDH decreases the production of the metabolite itaconate that is required for viral replication. With reduced OGDH and itaconate production in vivo, Alkbh5-deficient mice display innate immune response–independent resistance to viral exposure. Our findings reveal that m6A RNA modification–mediated down-regulation of the OGDH-itaconate pathway reprograms cellular metabolism to inhibit viral replication, proposing potential targets for controlling viral infection. ER -