Altered m6A Modification of Specific Cellular Transcripts Affects Flaviviridae Infection

Abstract

The RNA modification N⁶-methyladenosine (m⁶A) modulates mRNA fate and thus affects many biological processes. We analyzed m⁶A 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 m⁶A modification of specific cellular transcripts, including RIOK3 and CIRBP. During viral infection, the addition of m⁶A to RIOK3 promotes its translation, while loss of m⁶A in CIRBP promotes alternative splicing. Importantly, viral activation of innate immune sensing or the endoplasmic reticulum (ER) stress response contributes to the changes in m⁶A in RIOK3 or CIRBP, respectively. Further, several transcripts with infection-altered m⁶A 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 m⁶A modification of host mRNAs to regulate infection.

Keywords: CIRBP; ER stress; Flaviviridae; RIOK3; RNA modification; epitranscriptome; innate immunity; m(6)A; signaling; viral infection.