RNA-binding protein YTHDF3 suppresses interferon-dependent antiviral responses by promoting FOXO3 translation

Significance Type I IFN signaling is maintained under homeostatic conditions, which plays a crucial role in antiviral immunity. Epigenetic regulation of innate immunity and inflammation attracts much attention now. However, the underlying mechanisms need further investigation. Here, we demonstrate that N 6 -methyladenosine (m 6 A) “reader” YT521-B homology domain-containing family 3 (YTHDF3) selectively inhibits IFN-stimulated gene expression under basal conditions by binding to the translation initiation region of the transcription corepressor forkhead box protein O3 (FOXO3) mRNA and promoting its translation. Unexpectedly, the capacity of YTHDF3 for binding FOXO3 mRNA is independent of METTL3-mediated m 6 A modification. Our paper adds a view of YTHDF family proteins in the control of IFN antiviral responses. Overall, the roles of RNA-binding proteins and their RNA targets with certain modifications in inflammation and autoimmune diseases need further identification.