RNA-binding proteins like the m6A-binding family of YTHDF proteins are known to play a critical role in cancer development. We now uncovered autophagic regulation of YTHDF levels in cancer-relevant cellular states such as contact inhibition and differentiation.
Upon mTOR-mediated phosphorylation, YHTDF proteins interact with the autophagic machinery, are degraded, and co-sequester their m6A-RNA clients into autophagosomes. Our findings uncover a regulatory pathway that governs YTHDF protein stability with significant implications for cancer biology and cell fate determination and suggest the existence of an autophagy-mediated degradation pathway for m6A-modified RNA.