The N(6)-methyladenosine RNA-binding protein YTHDF1 modulates the translation of TRAF6 to mediate the intestinal immune response

The intestinal invasion of pathogenic microorganisms can have serious health consequences. Recent evidence has shown that the N(6)-methyladenosine (m(6)A) mRNA modification is closely associated with innate immunity; however, the underlying mechanism is poorly understood. Here, we examined the function and mechanism of m(6)A mRNA modification and the YTH domain-containing protein YTHDF1 (YTH N6-methyladenosine RNA-binding protein 1) in the innate immune response against bacterial pathogens in the intestine. Ribo-seq and m(6)A-seq analyses revealed that YTHDF1 directs the translation of Traf6 mRNA, which encodes tumor necrosis factor receptor-associated factor 6, thereby regulating the immune response via the m(6)A modification near the transcript's stop codon. Furthermore, we identified a unique mechanism by which the P/Q/N-rich domain in YTHDF1 interacts with the DEAD domain in the host factor DDX60, thereby regulating the intestinal immune response to bacterial infection by recognizing the target Traf6 transcript. These results provide novel insights into the mechanism by which YTHDF1 recognizes its target and reveal YTHDF1 as an important driver of the intestinal immune response, opening new avenues for developing therapeutic strategies designed to modulate the intestinal immune response to bacterial infection.