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

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

doi:10.1002/advs.202308786

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

Adv Sci (Weinh). 2024 May 2:e2308786. doi: 10.1002/advs.202308786. Online ahead of print.

Authors

Xinyi Zhou^{1

2}, Xiaoyu Yang¹, Shenzhen Huang³, Guifeng Lin⁴, Kexin Lei¹, Qian Wang¹, Weimin Lin¹, Hanwen Li¹, Xingying Qi⁵, Dutmanee Seriwatanachai⁶, Shengyong Yang⁴, Bin Shao¹, Quan Yuan¹

Affiliations

¹ State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
² Department of Prosthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai Jiao Tong University, Shanghai, 200011, China.
³ Henan Eye Institute, Henan Eye Hospital and Henan Key Laboratory of Ophthalmology and Visual Science, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, 450003, China.
⁴ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
⁵ Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology & Department of oral implantology, Stomatological Hospital and Dental School, Tongji University, Shanghai, 200072, China.
⁶ Department of Oral Biology, Faculty of Dentistry, Mahidol University, Bangkok, 10400, Thailand.

PMID: 38696610
DOI: 10.1002/advs.202308786

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.

Keywords: METTL3; m6A modification; periodontitis; pyroptosis; small‐molecule inhibitor.

Grants and funding

202111/WT_/Wellcome Trust/United Kingdom