Autophagy induction promoted by mA reader YTHDF3 through translation upregulation of FOXO3 mRNA.

Autophagy is crucial for maintaining cellular energy homeostasis and for cells to adapt to nutrient deficiency, and nutrient sensors regulating autophagy have been reported previously. However, the role of eiptranscriptomic modifications such as mA in the regulation of starvation-induced autophagy is unclear. Here, we show that the mA reader YTHDF3 is essential for autophagy induction. mA modification is up-regulated to promote autophagosome formation and lysosomal degradation upon nutrient deficiency. METTL3 depletion leads to a loss of functional mA modification and inhibits YTHDF3-mediated autophagy flux. YTHDF3 promotes autophagy by recognizing mA modification sites around the stop codon of FOXO3 mRNA. YTHDF3 also recruits eIF3a and eIF4B to facilitate FOXO3 translation, subsequently initiating autophagy. Overall, our study demonstrates that the epitranscriptome regulator YTHDF3 functions as a nutrient responder, providing a glimpse into the post-transcriptional RNA modifications that regulate metabolic homeostasis.