Deubiquitinase OTUD6a drives cardiac inflammation and hypertrophy by deubiquitination of STING

  • Biochim Biophys Acta Mol Basis Dis. 2024 Feb 9;1870(4):167061. doi: 10.1016/j.bbadis.2024.167061.
Zimin Fang  1 ,  Jibo Han  2 ,  Liming Lin  3 ,  Bozhi Ye  1 ,  Xuefeng Qu  4 ,  Yu Zhang  5 ,  Ying Zhao  3 ,  Diyun Xu  1 ,  Wante Lin  1 ,  Sirui Shen  6 ,  Julian Min  7 ,  Gaojun Wu  8 ,  Zhouqing Huang  9 ,  Guang Liang  10
Affiliations
  • 1. Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 2. Department of Cardiology, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China.
  • 3. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 4. School of Public Health, Hangzhou Medical College, Hangzhou, Zhejiang, China.
  • 5. Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 6. Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 7. School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.
  • 8. Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: [email protected].
  • 9. Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: [email protected].
  • 10. Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China. Electronic address: [email protected].
PMID: 38342418 DOI: 10.1016/j.bbadis.2024.167061
Abstract

Background: Cardiac hypertrophy is a crucial pathological characteristic of hypertensive heart disease and subsequent heart failure. Deubiquitinating Enzymes (DUBs) have been found to be involved in the regulation of myocardial hypertrophy. OTU Domain-Containing Protein 6a (OTUD6a) is a recently identified DUB. To date, the potential role of OTUD6a in myocardial hypertrophy has not yet been revealed.

Methods and results: We examined the up-regulated level of OTUD6a in mouse or human hypertrophic heart tissues. Then, transverse aortic constriction (TAC)- or angiotensin II (Ang II)- induced ventricular hypertrophy and dysfunction were significantly attenuated in OTUD6a gene knockout mice (OTUD6a-/-). In mechanism, we identified that the Stimulator of Interferon Genes (STING) is a direct substrate protein of OTUD6a via immunoprecipitation assay and mass spectrometry. OTUD6a maintains STING stability via clearing the K48-linked ubiquitin in cardiomyocytes. Subsequently, OTUD6a regulates the STING-downstream NF-κB signaling activation and inflammatory gene expression both in vivo and in vitro. Inhibition of STING blocked OTUD6a overexpression-induced inflammatory and hypertrophic responses in cardiomyocytes.

Conclusion: This finding extends our understanding of the detrimental role of OTUD6a in myocardial hypertrophy and identifies STING as a deubiquinating substrate of OTUD6a, indicating that targeting OTUD6a could be a potential strategy for the treatment of cardiac hypertrophy.

Keywords
Cardiac hypertrophy; Deubiquitination enzyme; Inflammation; OTU domain-containing protein 6a; Stimulator of interferon genes.
Products