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 N⁶-methyladenosine (m⁶A) is an adaptive β-cell safeguard mechanism that controls the amplitude and duration of the antiviral innate immune response at T1D onset. m⁶A writer methyltransferase 3 (METTL3) levels increase drastically in β-cells at T1D onset but rapidly decline with disease progression. m⁶A sequencing revealed the m⁶A hypermethylation of several key innate immune mediators, including OAS1, OAS2, OAS3 and ADAR1 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 T1D. 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 m⁶A regulates the innate immune response at the β-cell level during the onset of T1D in humans.

1 型糖尿病 (T1D) 的特点是胰腺 β 细胞遭到破坏。一些观察结果重新引起了人们对 β 细胞 RNA 传感器和编辑器的兴趣。在此，我们报道N ⁶ -甲基腺苷 (m ⁶ A) 是一种适应性 β 细胞保护机制，可控制 T1D 发病时抗病毒先天免疫反应的幅度和持续时间。m ⁶在 T1D 发病时，β 细胞中的 A writer 甲基转移酶 3 (METTL3) 水平急剧增加，但随着疾病进展迅速下降。m ⁶ A 测序揭示了几种关键先天免疫介质的m ^{6 A 高甲基化，包括 T1D 发病时人类胰岛和 EndoC-βH1 细胞中的}OAS1、OAS2、OAS3和ADAR1。METTL3 沉默通过增加 2'-5'-寡腺苷酸合成酶的 mRNA 稳定性来增强其水平。一致的是，在非肥胖 T1D 糖尿病小鼠模型中，延长 Mettl3 过度表达（特别是在 β 细胞中）的体内基因治疗可延缓糖尿病进展。从机制上讲，活性氧的积累阻止了 METTL3 响应细胞因子的上调，而生理水平的一氧化氮则增强了 METTL3 的水平和活性。此外，我们报道 METTL3 蛋白锌指结构域 C276 和 C326 位置的半胱氨酸对 S-亚硝基化敏感，并且对于 METTL3 介导的人 β 细胞中寡腺苷酸合酶 mRNA 稳定性的调节很重要。总的来说，我们报告 m ⁶ A 在人类 T1D 发病期间调节 β 细胞水平的先天免疫反应。