近日，美国芝加哥大学何川及哈佛医学院Rohit N. Kulkarni研究组发现，β-细胞中m6A甲基转移酶METTL3调控1型糖尿病的先天免疫反应。相关论文发表在2024年2月26日出版的《自然—细胞生物学》杂志上。

课题组报道N6 -甲基腺苷(m⁶A)是一种适应性β-细胞保护机制，控制T1D发病时抗病毒先天免疫反应的幅度和持续时间。m⁶A“书写者”甲基转移酶3 (METTL3)水平在T1D发病时在β-细胞中急剧升高，但随着疾病进展而迅速下降。m⁶A测序显示，在T1D发病时，人胰岛和内皮细胞-βH1细胞中几种关键的先天免疫介质，包括OAS1、OAS2、OAS3和ADAR1的m⁶A超甲基化。METTL3沉默通过增加2’-5‘-寡聚腺苷酸合成酶mRNA的稳定性来提高其水平。

与此一致的是，体内基因治疗延长Mettl3在β细胞中的过表达，延缓了非肥胖糖尿病模型T1D的糖尿病进展。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增强了METTL3的水平和活性。

此外，该课题组报道了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METTL3介导的人β细胞低聚腺苷酸合成酶mRNA稳定性的调节很重要。总的来说，课题组研究人员报告了m6A在人类T1D发病期间在β细胞水平调节先天免疫反应。

据介绍，1型糖尿病(T1D)的特征是胰腺β细胞的破坏。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。

附：英文原文

Title: Redox regulation of m6A methyltransferase METTL3 in β-cells controls the innate immune response in type 1 diabetes

Author: F. De Jesus, Dario, 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.

Issue&Volume: 2024-02-26

Abstract: 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.

DOI: 10.1038/s41556-024-01368-0

Source: https://www.nature.com/articles/s41556-024-01368-0