Journal
CELLULAR SIGNALLING
Volume 87, Issue -, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2021.110118
Keywords
p62; SQSTM1; Autophagy; Ubiquitylation; Myocardial ischemia-reperfusion injury
Categories
Funding
- Natural Science Foundation of China [31760292, 81760087, 81560050]
- Department of Science and Technology of Yunnan Province [2017FA035, 202101AT070179, 2017FE467 (-008)]
- Provincial Major Special Projects [2019ZF011-2]
- Program for Innovative Research Team (in Science and Technology) in the University of Yunnan Province
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In this study, it was found that UBE2D3 promoted p62 ubiquitination to aggravate the impairment of autophagic flux induced by myocardial I/R injury, while mTOR was also involved in regulating autophagic flux in a way independent of the beclin1 pathway.
The impairment of autophagic flux has been widely recognized in myocardial ischemia-reperfusion (I/R) injury, but its underlying mechanism contributing to impaired autophagic flux is poorly understood. As celluar major degradation systems, autophagy and ubiquitin proteasome system (UPS) participate in the multitudinous pro-gression of disease by interactive relationship. Especially UBE2D3, one of the ubiquitin-binding enzyme E2 family, is closely related to the regulation impairment of autophagic flux under I/R in our study. Therefore, this study aims to further explore the regulatory mechanism of UBE2D3 in I/R induced autophagy. We determined interference with UBE2D3 alleviated injury of myocardial cells both in vivo and in vitro. Conversely, when inhibiting proteasome function by injecting MG-132, myocardial infarct size of rats became increasingly enhanced, along with the high expression levels of LDH and CK-MB in serum, compared with myocardial I/R injury without treatment of MG-132. This had been caused by UBE2D3 promoting p62/SQSTM1(p62) ubiq-uitination(Ub), which lead to worsen the impairment of autophagic flux induced by myocardial I/R injury. In addition, UBE2D3 could also participate in the regulation of autophagy by negatively regulating mTOR. But more surprisingly, this mechanism was independent of the known mTOR-beclin1 pathway. These results suggested that in myocardial I/R injury, UBE2D3 promoted p62 ubiquitination to aggravate the impairment of autophagic flux. Moreover, mTOR was also involved in its regulation of autophagic flux in a way escaped from beclin1.
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