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

Cell Research volume 33, pages 546–561 (2023)Cite this article

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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.

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Fig. 1: S-nitrosylation of CTSB at a phylogenetically conserved cysteine.
Fig. 2: S-nitrosylation of CTSB increases the steady-state levels of its own protein via mRNA stabilization.
Fig. 3: S-nitrosylation of CTSB controls its own RNA editing to promote CTSB mRNA stability via recruiting HuR.
Fig. 4: Matrin-3 binds to CTSB mRNA and recruits ADAR1 for CTSB mRNA editing.
Fig. 5: S-nitrosylation of CTSB promotes nuclear translocation of ADD1 to recruit MATR3/ADAR1.
Fig. 6: S-nitrosylation of CTSB and CTSB mRNA editing may be critically involved in vascular diseases.
Fig. 7: Schematic diagram showing the proposed mechanistic model of “PEDORA”.

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Acknowledgements

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).

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Author notes

  1. These authors contributed equally: Zhe Lin, Shuang Zhao, Xuesong Li.

Authors and Affiliations

  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

    Zhe Lin, Shuang Zhao, Xuesong Li, Zian Miao, Jiawei Cao, Yurong Chen, Zhiguang Shi, Jia Zhang, Liping Xie, Hongshan Chen & Yong Ji

  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

    Dongjin Wang

  3. Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China

    Shaoliang Chen

  4. Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China

    Liansheng Wang

  5. State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China

    Aihua Gu

  6. Department of Forensic Medicine, Nanjing Medical University, Nanjing, Jiangsu, China

    Feng Chen

  7. Department of Endocrinology and Metabolism, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China

    Tao Yang

  8. Department of Cardiology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China

    Kangyun Sun

  9. Department of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China

    Yi Han

  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

    Yong Ji

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  1. Zhe Lin
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Contributions

Y.J. and H.C. designed the research. Z.L., S.Z., X.L., and Y.H. designed the experiments. Z.L., S.Z., X.L., Z.M., J.C., Y.C., Z.S., and J.Z. performed the experiments. Z.L., S.Z., Z.M., A.G., and F.C. analyzed the data. Z.L., S.Z., X.L., and Z.M. wrote the manuscript. D.W., S.C., L.W., T.Y., and K.S. provided the clinical samples. All authors discussed and commented on the manuscript.

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Correspondence to Yi Han, Liping Xie, Hongshan Chen or Yong Ji.

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Lin, Z., Zhao, S., Li, X. et al. Cathepsin B S-nitrosylation promotes ADAR1-mediated editing of its own mRNA transcript via an ADD1/MATR3 regulatory axis. Cell Res 33, 546–561 (2023). https://doi.org/10.1038/s41422-023-00812-4

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