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在纤维化中METTL3-介导的N 6 -Methyladenosine mRNA修饰和cGAS-STING通路活性

Yu-Cheng Tsai^1,2, Tsung-Han Hsieh³, Yuan-Ru Liao^1,2

¹Division of Nephrology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.

Journal of the American Society of Nephrology : JASN

|October 1, 2024

概括

慢性病 (CKD) 脏中增加的N6-甲基氨酸 (m6A) RNA修饰和METTL3表达激活炎症通路,驱动纤维化. 降低m6A水平可以防止病的进展.

科学领域:

生物化学生物化学
分子生物学分子生物学
病理学病理学病理学

背景情况:

N6-甲基氨酸 (m6A) 是真核生物中最丰富的RNA修饰,对RNA功能和调节至关重要.
虽然m6A在细胞过程和疾病中的作用是公认的,但它对人类慢性病 (CKD) 病理机制的具体影响仍未得到充分研究.
这项研究研究了m6A修饰在病进展中的作用.

研究的目的:

研究人类CKD样本中m6A水平和模式的变化.
阐明m6A修饰的功能作用,特别是由METTL3介导,在管细胞和CKD病原体中的功能作用.
探索脏疾病中针对m6A修饰的治疗潜力.

主要方法:

液体染色学并联质谱学和甲基化RNA免疫沉测序被用来分析CKD样本中的m6A变化.
为了研究m6A的作用,METTL3在管细胞中过度表达,其表达在体内使用管体特异性删除 (Ksp-Cre Mettl3f/f小鼠) 和反感性寡核化物进行了操纵.
经上转录组分析确定了m6A修饰的转录和相关的信号通路.

主要成果:

在127个人类CKD样本中观察到m6A修饰和METTL3表达的显著增加.
在m6A高甲基化中,IFN基因 (STING) 途径的循环瓜诺辛单酸AMP合成酶 (cGAS) 刺激器的转录被丰富,增加了cGAS和STING1.1的mRNA稳定性.
在小鼠中抑制METTL3减轻了脏炎症,减少了细胞因子表达,减少了免疫细胞透,并减轻了纤维化.

结论:

增强的METTL3介导的m6A修饰是纤维化脏的关键特征,特别是促进cGAS-STING通路.
这种m6A高甲基化增强了cGAS和STING1mRNA的稳定性,导致无菌炎症和纤维化.
向METTL3介导的m6A修饰是一种潜在的治疗策略,可以缓解纤维化和炎症.

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