2. Academic Validation
  3. YTHDF2 regulates self non-coding RNA metabolism to control inflammation and tumorigenesis

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

  • Nat Commun. 2025 Nov 12;16(1):9946. doi: 10.1038/s41467-025-64898-7.
Seungwon Yang # 1,  Yan-Hong Cui # 2,  Haixia Li # 2,  Jiangbo Wei # 3,  Gayoung Park 2,  Ming Sun 2,  Michelle Verghese 2,  Emma Wilkinson 2,  Teresa Nam 4,  Linnea Louise Lungstrom 4,  Xiaolong Cui 3,  Tae Young Ryu 2,  Jing Chen 5,  Marc Bissonnette 6,  Chuan He 3 7,  Yu-Ying He 8
Affiliations

Affiliations

  • 1 Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL, USA. [email protected].
  • 2 Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL, USA.
  • 3 Departments of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, University of Chicago, Chicago, IL, USA.
  • 4 The College, University of Chicago, Chicago, IL, USA.
  • 5 Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, USA.
  • 6 Department of Medicine, Section of Gastroenterology, Hepatology & Nutrition, University of Chicago, Chicago, IL, USA.
  • 7 Howard Hughes Medical Institute, University of Chicago, Chicago, IL, USA.
  • 8 Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL, USA. [email protected].
  • # Contributed equally.
PMID: 41224760 DOI: 10.1038/s41467-025-64898-7
Abstract

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.

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