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

Area of Science:

• Immunology
• Molecular Biology
• RNA Biology

Background:

• The function of m⁶A RNA methylation in self non-coding RNA is largely unknown.
• Toll-like receptor 3 (TLR3) plays a role in inflammatory responses.

Purpose of the Study:

• To investigate the role of m⁶A-methylated U6 small nuclear RNA (snRNA) in regulating inflammatory responses.
• To elucidate the mechanism by which YTH domain-containing family protein 2 (YTHDF2) interacts with U6 snRNA and TLR3.

Main Methods:

• Utilized human and mouse cell lines and mouse models.
• Investigated the interaction between U6 snRNA, YTHDF2, and TLR3 using molecular biology techniques.
• Examined the effect of UVB exposure on YTHDF2 activity.
• Assessed the impact of Ythdf2 deletion on inflammatory responses and tumor initiation in mice.

Main Results:

• m⁶A-methylated U6 snRNA is recognized by YTHDF2, which reduces U6 snRNA stability and prevents its binding to TLR3.
• U6 snRNA activates inflammatory gene expression by binding to the LRR21 domain of TLR3 in endosomes.
• YTHDF2, localized to endosomes via SIDT2, inhibits U6-TLR3 interaction.
• UVB exposure degrades YTHDF2, enhancing inflammatory responses and promoting tumor initiation in mice lacking skin Ythdf2.

Conclusions:

• YTHDF2 is crucial for controlling inflammation by inhibiting m⁶A U6-mediated TLR3 activation.
• YTHDF2 and m⁶A U6 represent potential therapeutic targets for inflammation and tumorigenesis.