Redox regulation of m 6 A methyltransferase METTL3 in β-cells controls the innate immune response in type 1 diabetes

• Published in: Nature cell biology Vol. 26; no. 3; p. 421
• Main Authors: De Jesus, Dario F, Zhang, Zijie, Brown, Natalie K, Li, Xiaolu, Xiao, Ling, Hu, Jiang, Gaffrey, Matthew J, Fogarty, Garrett, Kahraman, Sevim, Wei, Jiangbo, Basile, Giorgio, Rana, Tariq M, Mathews, Clayton, Powers, Alvin C, Parent, Audrey V, Atkinson, Mark A, Dhe-Paganon, Sirano, Eizirik, Decio L, Qian, Wei-Jun, He, Chuan, Kulkarni, Rohit N
• Format: Journal Article
• Language: English
• Published: England 01.03.2024
• ISSN: 1476-4679

Type 1 diabetes (T1D) is characterized by the destruction of pancreatic β-cells. Several observations have renewed the interest in β-cell RNA sensors and editors. Here, we report that -methyladenosine (m A) is an adaptive β-cell safeguard mechanism that controls the amplitude and duration of the antiviral innate immune response at T1D onset. m A writer methyltransferase 3 (METTL3) levels increase drastically in β-cells at T1D onset but rapidly decline with disease progression. m A sequencing revealed the m A hyper methylation of several key innate immune mediators, including , , and in human islets and EndoC-βH1 cells at T1D onset. METTL3 silencing enhanced 2'-5'-oligoadenylate synthetase levels by increasing its mRNA stability. Consistently, in vivo gene therapy to prolong Mettl3 overexpression specifically in β-cells delayed diabetes progression in the non-obese diabetic mouse model of T1 D. Mechanistically, the accumulation of reactive oxygen species blocked upregulation of METTL3 in response to cytokines, while physiological levels of nitric oxide enhanced METTL3 levels and activity. Furthermore, we report that the cysteines in position C276 and C326 in the zinc finger domains of the METTL3 protein are sensitive to S-nitrosylation and are important to the METTL3-mediated regulation of oligoadenylate synthase mRNA stability in human β-cells. Collectively, we report that m A regulates the innate immune response at the β-cell level during the onset of T1D in humans.