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

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

机构地区：[1]Key Laboratory of Cardiovascular and Cerebrovascular Medicine,Key Laboratory of Targeted Intervention of Cardiovascular Disease,Collaborative Innovation Center for Cardiovascular Disease Translational Medicine,State Key Laboratory of Reproductive Medicine,School of Pharmacy,the Affiliated Suzhou Hospital of Nanjing Medical University,Gusu School,Nanjing Medical University,Nanjing,Jiangsu,China [2]Department of Thoracic and Cardiovascular Surgery,the Affiliated Drum Tower Hospital of Nanjing University Medical School,Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University,Institute of Cardiothoracic Vascular Disease,Nanjing University,Nanjing,Jiangsu,China [3]Department of Cardiology,Nanjing First Hospital,Nanjing Medical University,Nanjing,Jiangsu,China [4]Department of Cardiology,the First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu,China [5]State Key Laboratory of Reproductive Medicine,Institute of Toxicology,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu,China [6]Department of Forensic Medicine,Nanjing Medical University,Nanjing,Jiangsu,China [7]Department of Endocrinology and Metabolism,the First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu,China [8]Department of Cardiology,the Affiliated Suzhou Hospital of Nanjing Medical University,Suzhou Municipal Hospital,Gusu School,Nanjing Medical University,Suzhou,Jiangsu,China [9]Department of Geriatrics,the First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu,China [10]National Key Laboratory of Frigid Zone Cardiovascular Diseases(NKLFZCD),Department of Pharmacology(State-Province Key Laboratories of Biomedicine-Pharmaceutics of China),College of Pharmacy,Key Laboratory of Cardiovascular Medicine Research and Key Laboratory of Myocardial Ischemia,Chinese Ministry of Education,NHC Key Laboratory of Cell Transplantation,the Central Laboratory of the First Affiliated Hospital,Harbin Medical University,Harbin,Heilongjiang,China

出　　处：《Cell Research》2023年第7期546-561,共16页细胞研究（英文版）

基　　金：This work was supported by grants from the National Natural Science Foundation of China(82121001,82030013,91639204,82241211,81820108002,82270421,81970428,31771334,91649125,81900262,82100414,81800385,82270484),the National Key R&D Program of China(2019YFA0802704),and Jiangsu Provincial Natural Science Foundation(BK20190656).

摘　　要：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.

关 键 词：ADAR1 MEDIATED EDITING 

分 类 号：Q2[生物学—细胞生物学]