N?6-methyladenosine?RNA?modification-mediated?cellular?metabolism?rewiring?inhibits?viralreplication

Liu Y1,2, You Y1, Lu Z3, Yang J1, Li P1, Liu L1, Xu H1, Niu Y4, Cao X5,2,6

Science. 2019 Aug 22. pii: eaax4468.

PMID: 31439758

Abstract

Host cell metabolism can be modulated by viral infection, affecting viral survival or clearance. The cellular metabolism rewiring mediated by N 6-methyladenosine (m6A) 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 m6A demethylase ALKBH5. This increases the m6A 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 m6A RNA modification-mediated down-regulation of OGDH-Itaconate pathway reprograms cellular metabolism to inhibit viral replication, proposing potential targets for controlling viral infection.