Altered m6A Modification of Specific Cellular Transcripts Affects Flaviviridae Infection

The RNA modification N-6-methyladenosine (m(6)A) modulates mRNA fate and thus affects many biological processes. We analyzed m(6)A across the transcriptome following infection by dengue virus (DENV), Zika virus (ZIKV), West Nile virus (WNV), and hepatitis C virus (HCV). We found that infection by these viruses in the Flaviviridae family alters m(6)A modification of specific cellular transcripts, including RIOK3 and CIRBP. During viral infection, the addition of m(6)A to RIOK3 promotes its translation, while loss of m(6)A in CIRBP promotes alternative splicing. Importantly, viral activation of innate immune sensing or the endoplasmic reticulum (ER) stress response contributes to the changes in m(6)A in RIOK3 or CIRBP, respectively. Further, several transcripts with infection-altered m(6)A profiles, including RIOK3 and CIRBP, encode proteins that influence DENV, ZIKV, and HCV infection. Overall, this work reveals that cellular signaling pathways activated during viral infection lead to alterations in m(6)A modification of host mRNAs to regulate infection.