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. RNA modifications influence gene regulation and disease. Here, the authors show that YTHDF2 recognizes m6A-modified U6 snRNA to prevent aberrant TLR3 activation to inhibit inflammation and skin cancer development.

• Publication year

  2025

• Venue

  Nature Communications

• Publication date

  2025-11-12

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/s41467-025-64898-7PMID 41224760PMCID 12612255
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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