Tsg101 positively regulates P62-Keap1-Nrf2 pathway to protect hearts against oxidative damage
Shan Deng,
Kobina Essandoh,
Xiaohong Wang,
Yutian Li,
Wei Huang,
Jing Chen,
Jiangtong Peng,
Ding-Sheng Jiang,
Xingjiang Mu,
Chenran Wang,
Tianqing Peng,
Jun-Lin Guan,
Yigang Wang,
Anil Jegga,
Kai Huang,
Guo-Chang Fan
Affiliations
Shan Deng
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China; Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Clinical Center for Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
Kobina Essandoh
Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
Xiaohong Wang
Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
Yutian Li
Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
Wei Huang
Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
Jing Chen
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
Jiangtong Peng
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China; Clinical Center for Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
Ding-Sheng Jiang
Division of Cardiothoracic and Vascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
Xingjiang Mu
Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
Chenran Wang
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
Tianqing Peng
Critical Illness Research, Lawson Health Research Institute, Ontario, Canada
Jun-Lin Guan
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
Yigang Wang
Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
Anil Jegga
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
Kai Huang
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China; Clinical Center for Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
Guo-Chang Fan
Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Corresponding author. Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, 45267-0575, USA.
Currently, most antioxidants do not show any favorable clinical outcomes in reducing myocardial ischemia-reperfusion (I/R) injury, suggesting an urgent need for exploring a new regulator of redox homeostasis in I/R hearts. Here, using heart-specific transgenic (TG) and knockdown (KD) mouse models, tumor susceptibility gene 101 (Tsg101) is defined as a novel cardiac-protector against I/R-triggered oxidative stress. RNA sequencing and bioinformatics data surprisingly reveal that most upregulated genes in Tsg101-TG hearts are transcribed by Nrf2. Accordingly, pharmacological inhibition of Nrf2 offsets Tsg101-elicited cardio-protection. Mechanistically, Tsg101 interacts with SQSTM1/p62 through its PRR domain, and promotes p62 aggregation, leading to recruitment of Keap1 for degradation by autophagosomes and release of Nrf2 to the nucleus. Furthermore, knockout of p62 abrogates Tsg101-induced cardio-protective effects during I/R. Hence, our findings uncover a previously unrecognized role of Tsg101 in the regulation of p62/Keap1/Nrf2 signaling cascades and provide a new strategy for the treatment of ischemic heart disease.
