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

Zhe Lin^1,† , Shuang Zhao^1,† , Xuesong Li^1,† , 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 Han^9,* , Liping Xie^1,* , Hongshan Chen^1,* , Yong Ji^1,10,*

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
²Department 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
³Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
⁴Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
⁵State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
⁶Department of Forensic Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
⁷Department of Endocrinology and Metabolism, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
⁸Department of Cardiology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China
⁹Department of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
¹⁰National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Department of Pharmacology (State-Province Key Laboratories of BiomedicinePharmaceutics 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
^†These authors contributed equally: Zhe Lin, Shuang Zhao, Xuesong Li
* Correspondence: Yi Han(hanyi@jsph.org.cn)Liping Xie(lipingxie@njmu.edu.cn)Hongshan Chen(hongshanchen@njmu.edu.cn)Yong Ji(yongji@hrbmu.edu.cn)

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.

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

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