2. Academic Validation
  3. Deubiquitinase OTUD6a drives cardiac inflammation and hypertrophy by deubiquitination of STING

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

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: gaojunwuwyyy@163.com.
  • 9 Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: susiehzq@126.com.
  • 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: wzmcliangguang@163.com.
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.

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