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

The role of m<sup>6</sup>A RNA methylation of self non-coding RNA remains poorly understood. Here we show that m<sup>6</sup>A-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 m<sup>6</sup>A 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 m<sup>6</sup>A U6-mediated TLR3 activation, suggesting that YTHDF2 and m<sup>6</sup>A U6 are potential therapeutic targets for preventing and treating inflammation and tumorigenesis.

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Publication Details

Journal
Nature Communications
Published
2025-11-12
DOI
https://doi.org/10.1038/s41467-025-64898-7
Citations
2
Primary Topic
RNA modifications and cancer
Type
article
Field-Weighted Citation Impact
1.61

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article

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

Seungwon Yang, Marc Bissonnette, Michelle Verghese, Yu‐Ying He et al.
2 citations
Nature Communications
RNA modifications and cancer
1.61
article

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

Seungwon Yang, Marc Bissonnette, Michelle Verghese, Yu‐Ying He, Yan‐Hong Cui, Jiangbo Wei, Tae Young Ryu, Emma Wilkinson, Linnea L. Lungstrom, Tae Gyu Nam, Chuan He, Jing Chen, Haixia Li, Ming Sun, Xiao‐Long Cui, Gayoung Park
article en
2 citations

Abstract

The role of m<sup>6</sup>A RNA methylation of self non-coding RNA remains poorly understood. Here we show that m<sup>6</sup>A-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 m<sup>6</sup>A 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 m<sup>6</sup>A U6-mediated TLR3 activation, suggesting that YTHDF2 and m<sup>6</sup>A U6 are potential therapeutic targets for preventing and treating inflammation and tumorigenesis.

Nature CommunicationsVol. 16(1)
Howard Hughes Medical Institute (US), University of Illinois Chicago (US), University of Chicago (US)
Howard Hughes Medical Institute, Georgia Clinical and Translational Science Alliance, National Institutes of Health, Hospitality and Tourism Research Centre, Hong Kong Polytechnic University
Openalex Percentile: Top 14%
RNA modifications and cancer
1.61
DOIOpen Access PDFOpenAlex
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