N6-methyladenosine modification of the mRNA for a key gene in purine nucleotide metabolism regulates virus proliferation in an insect vector

The titer of viruses that persist and propagate in their insect vector must be high enough for transmission yet not harm the insect, but the mechanism of this dynamic balance is unclear. Here, expression of inosine monophosphate dehydrogenase (LsIMPDH), a rate-limiting enzyme for guanosine triphosphate (GTP) synthesis, is shown to be downregulated by increased levels of N6-methyladenosine (m6A) on LsIMPDH mRNA in rice stripe virus (RSV)-infected small brown planthoppers (SBPHs; Laodelphax striatellus), the RSV vector, which decreases GTP content, thus limiting viral proliferation. Moreover, planthopper methyltransferase-like protein 3 (LsMETTL3) and m6A reader protein LsYTHDF3 are found to catalyze and recognize the m6A on LsIMPDH mRNA, respectively, and cooperate in destabilizing LsIMPDH transcripts. Co-silencing assays show that negative regulation of viral proliferation by both LsMETTL3 and LsYTHDF3 is partially dependent on LsIMPDH. This distinct mechanism limits virus replication in an insect vector, providing a potential gene target to block viral transmission. [Display omitted] •LsIMPDH expression is downregulated in RSV-infected SBPH, which decreases GTP content•Upregulation of LsMETTL3 by RSV results in an increase in m6A on LsIMPDH mRNAs•Recognition of m6A in LsIMPDH mRNAs by LsYTHDF3 promotes decay of LsIMPDH transcripts•Lower GTP limits viral replication in SBPH, leading to inefficient transmission Zhu et al. show that the expression of LsIMPDH, regulated by LsMETTL3 and LsYTHDF3 via m6A catalysis and recognition, respectively, is reduced in rice stripe virus (RSV)-infected small brown planthoppers (SBPHs). Reduction in LsIMPDH decreases GTP content and limits viral proliferation in SBPHs, thus preventing RSV transmission to rice plants.