2023年5月8日出版的《细胞研究》杂志发表了南京医科大学Yong Ji、Hongshan Chen、Liping Xie和Yi Han课题组合作的最新研究成果。他们发现组织蛋白酶B S-亚硝基化通过ADD1/MATR3调节通路促进ADAR1介导的对其自身mRNA转录本进行编辑。

研究人员发现蛋白质翻译后修饰能特异性实现对其自身mRNA进行编辑。研究表明组织蛋白酶B（CTSB）的S-亚硝基化对其自身mRNA特异性产生腺苷到肌苷（A-to-I）的编辑。在机制上，CTSB S-亚硝基化促进ADD1的去磷酸化和核易位，从而招募MATR3和ADAR1到CTSB mRNA。ADAR1介导的A-to-I RNA编辑使HuR能够与CTSB mRNA结合，从而提高CTSB mRNA的稳定性，进而提高CTSB蛋白的稳态水平。研究人员发现了由ADD1/MATR3/ADAR1调节轴介导的蛋白质表达调节特异性前反馈机制。

该研究表明，从蛋白质翻译后修饰到对其自身mRNA前体的转录后调节，这是一种新的信息逆流。研究人员将这一过程称为“ADAR1（PEDORA）对其自身mRNA的蛋白质定向编辑”，并认为这是蛋白质表达调控的额外机制。“PEDORA”可能是真核基因表达调控的隐藏机制。

据介绍，遗传信息一般通过经典的“中心法则”从RNA翻译为蛋白质。

附：英文原文

Title: Cathepsin B S-nitrosylation promotes ADAR1-mediated editing of its own mRNA transcript via an ADD1/MATR3 regulatory axis

Author: Lin, Zhe, Zhao, Shuang, Li, Xuesong, Miao, Zian, Cao, Jiawei, Chen, Yurong, Shi, Zhiguang, Zhang, Jia, Wang, Dongjin, Chen, Shaoliang, Wang, Liansheng, Gu, Aihua, Chen, Feng, Yang, Tao, Sun, Kangyun, Han, Yi, Xie, Liping, Chen, Hongshan, Ji, Yong

Issue&Volume: 2023-05-08

Abstract: Genetic information is generally transferred from RNA to protein according to the classic “Central Dogma”. Here, we made a striking discovery that post-translational modification of a protein specifically regulates the editing of its own mRNA. We show that S-nitrosylation of cathepsin B (CTSB) exclusively alters the adenosine-to-inosine (A-to-I) editing of its own mRNA. Mechanistically, CTSB S-nitrosylation promotes the dephosphorylation and nuclear translocation of ADD1, leading to the recruitment of MATR3 and ADAR1 to CTSB mRNA. ADAR1-mediated A-to-I RNA editing enables the binding of HuR to CTSB mRNA, resulting in increased CTSB mRNA stability and subsequently higher steady-state levels of CTSB protein. Together, we uncovered a unique feedforward mechanism of protein expression regulation mediated by the ADD1/MATR3/ADAR1 regulatory axis. Our study demonstrates a novel reverse flow of information from the post-translational modification of a protein back to the post-transcriptional regulation of its own mRNA precursor. We coined this process as “Protein-directed EDiting of its Own mRNA by ADAR1 (PEDORA)” and suggest that this constitutes an additional layer of protein expression control. “PEDORA” could represent a currently hidden mechanism in eukaryotic gene expression regulation.

DOI: 10.1038/s41422-023-00812-4

Source: https://www.nature.com/articles/s41422-023-00812-4