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.
Subject(s)
Inflammasomes , Methyltransferases , NIMA-Related Kinases , Ubiquitination , NIMA-Related Kinases/genetics , NIMA-Related Kinases/metabolism , Animals , Methyltransferases/metabolism , Methyltransferases/genetics , Mice , Inflammasomes/metabolism , Inflammasomes/genetics , Ubiquitination/drug effects , Ubiquitination/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Disease Models, Animal , Periodontitis/genetics , Periodontitis/metabolism , Periodontitis/drug therapy , Mice, Inbred C57BL , HumansABSTRACT
METTL5 is a methyltransferase that mediates eukaryotic 18S ribosomal RNA m6A modification, and its mutations lead to intellectual disability, microcephaly, and facial dysmorphism in patients. However, the role of METTL5 in craniofacial development remains poorly understood. This study demonstrates that Mettl5 knockout mice exhibit poor ossification, widened cranial sutures, and a cleidocranial dysplasia-like phenotype. Deletion of Mettl5 leads to increased proliferation and decreased osteogenic differentiation of suture mesenchymal stem cells. Mechanistically, we find that Wnt signaling is significantly downregulated after Mettl5 knockout. Overall, we reveal an essential role of METTL5 in craniofacial development and osteogenic differentiation of suture mesenchymal stem cells, making METTL5 a potential diagnostic and therapeutic target for craniofacial developmental diseases.