Volume 33, No 7, Jul 2023
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 33 Issue 7, July 2023: 546-561
Cathepsin B S-nitrosylation promotes ADAR1-mediated editing of its own mRNA transcript via an ADD1/MATR3 regulatory axis
Zhe Lin1,? , Shuang Zhao1,? , Xuesong Li1,? , Zian Miao1 , Jiawei Cao1 , Yurong Chen1 , Zhiguang Shi1 , Jia Zhang1 , Dongjin Wang2 , Shaoliang Chen3 , Liansheng Wang4 , Aihua Gu5 , Feng Chen6 , Tao Yang7 , Kangyun Sun8 , Yi Han9,* , Liping Xie1,* , Hongshan Chen1,* , Yong Ji1,10,*1Key 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
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.