YTHDF2 regulates self non-coding RNA metabolism to control inflammation and tumorigenesis

The role of m⁶A RNA methylation of self non-coding RNA remains poorly understood. Here we show that m⁶A-methylated self U6 snRNA is recognized by YTHDF2 to reduce its stability and prevent its binding to Toll-like receptor 3 (TLR3), leading to decreased inflammatory responses in human and mouse cells and mouse models. At the molecular level, endosomal U6 snRNA binds to the LRR21 domain in TLR3, independent of m⁶A methylation, to activate inflammatory gene expression, a mechanism that is distinct from that of the best known synthetic TLR3 agonist poly I:C. Both U6 snRNA and YTHDF2 are localized to endosomes via the transmembrane protein SIDT2, where YTHDF2 functions to prevent the U6-TLR3 interaction. We further show that UVB exposure inhibits YTHDF2 by inducing its dephosphorylation and autophagic protein degradation in human keratinocytes and mouse skin. Skin-specific deletion of Ythdf2 in mice enhanced the UVB-induced skin inflammatory response and promoted tumor initiation. Taken together, our findings demonstrate that YTHDF2 plays a crucial role in controlling inflammation by inhibiting m⁶A U6-mediated TLR3 activation, suggesting that YTHDF2 and m⁶A U6 are potential therapeutic targets for preventing and treating inflammation and tumorigenesis.