Inhibition of METTL3 Alleviates NLRP3 Inflammasome Activation via Increasing Ubiquitination of NEK7
Issued Date
2024-01-01
Resource Type
eISSN
21983844
Scopus ID
2-s2.0-85191712172
Journal Title
Advanced Science
Rights Holder(s)
SCOPUS
Bibliographic Citation
Advanced Science (2024)
Suggested Citation
Zhou X., Yang X., Huang S., Lin G., Lei K., Wang Q., Lin W., Li H., Qi X., Seriwatanachai D., Yang S., Shao B., Yuan Q. Inhibition of METTL3 Alleviates NLRP3 Inflammasome Activation via Increasing Ubiquitination of NEK7. Advanced Science (2024). doi:10.1002/advs.202308786 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/98295
Title
Inhibition of METTL3 Alleviates NLRP3 Inflammasome Activation via Increasing Ubiquitination of NEK7
Corresponding Author(s)
Other Contributor(s)
Abstract
N6-methyladenosine (m6A) modification, installed by METTL3-METTL14 complex, is abundant and critical in eukaryotic mRNA. However, its role in oral mucosal immunity remains ambiguous. Periodontitis is a special but prevalent infectious disease characterized as hyperinflammation of oral mucosa and bone resorption. Here, it is reported that genetic deletion of Mettl3 alleviates periodontal destruction via suppressing NLRP3 inflammasome activation. Mechanistically, the stability of TNFAIP3 (also known as A20) transcript is significantly attenuated upon m6A modification. When silencing METTL3, accumulated TNFAIP3 functioning as a ubiquitin-editing enzyme facilitates the ubiquitination of NEK7 [NIMA (never in mitosis gene a)-related kinase 7], and subsequently impairs NLRP3 inflammasome assembly. Furtherly, Coptisine chloride, a natural small-molecule, is discovered as a novel METTL3 inhibitor and performs therapeutic effect on periodontitis. The study unveils a previously unknown pathogenic mechanism of METTL3-mediated m6A modifications in periodontitis and indicates METTL3 as a potential therapeutic target.