YTHDF1 drives intestinal immune response against bacterial infection

Invasion of pathogenic bacteria is a serious threat to intestinal health. Recent emerging evidence has demonstrated that N6-methyladenosine (mA) is closely associated with innate immunity; however, the underlying mechanism remains unclear. Herein, we aim to explore the function and mechanism of mA modification in the regulation of innate immune responses against bacterial pathogens in the intestine. Ribo-seq and mA-seq data have demonstrated that YTHDF1, an mA reader, directs the translation of tumor necrosis factor receptor-associated factor 6 (TRAF6) mRNA to regulate immune responses via modulation of mA methylation near stop codon. Furthermore, we have identified a unique mechanism that the interaction between YTHDF1 and the host factor DDX60 are critical in regulating intestinal immune response against bacterial infection by recognizing TRAF6 target transcripts. Additionally, our results provide novel insights as to why YTHDF1 could recognize its unique targets using the same domain as other YTHDF proteins. This work identifies YTHDF1 as a key driver of intestinal immune responses and provides an avenue for development of novel strategies to modulate intestinal immune response against bacterial infection.