Inhibition of METTL3 Alleviates NLRP3 Inflammasome Activation Via Increasing Ubiquitination of NEK7

Overview

Journal Adv Sci (Weinh)

Specialty Biomedical Engineering

Date 2024 May 2

PMID 38696610

Authors

Xinyi Zhou

Xiaoyu Yang

Shenzhen Huang

Guifeng Lin

Kexin Lei

Qian Wang

Weimin Lin

Hanwen Li

Xingying Qi

Dutmanee Seriwatanachai

Shengyong Yang

Bin Shao

Quan Yuan

Affiliations

Soon will be listed here.

Abstract

N6-methyladenosine (mA) 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 mA 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 mA modifications in periodontitis and indicates METTL3 as a potential therapeutic target.

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