Tripartite motif 25 ameliorates doxorubicin-induced cardiotoxicity by degrading p85α

Yihui Shen; Hui Zhang; Yangyue Ni; Xuejun Wang; Yifan Chen; Jiahui Chen; Yan Wang; Jinyi Lin; Yuchen Xu; Jian-Yuan Zhao; Leilei Cheng

doi:10.1038/s41419-022-05100-4

Cell Death and Disease (Jul 2022)

Tripartite motif 25 ameliorates doxorubicin-induced cardiotoxicity by degrading p85α

Yihui Shen,
Hui Zhang,
Yangyue Ni,
Xuejun Wang,
Yifan Chen,
Jiahui Chen,
Yan Wang,
Jinyi Lin,
Yuchen Xu,
Jian-Yuan Zhao,
Leilei Cheng

Affiliations

Yihui Shen: Department of Echocardiography, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai Institute of Medical Imaging
Hui Zhang: Department of Echocardiography, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai Institute of Medical Imaging
Yangyue Ni: State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences
Xuejun Wang: Department of Echocardiography, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai Institute of Medical Imaging
Yifan Chen: Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases
Jiahui Chen: Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases
Yan Wang: Department of Medical Oncology, Zhongshan Hospital, Fudan University
Jinyi Lin: Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases
Yuchen Xu: Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases
Jian-Yuan Zhao: Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
Leilei Cheng: Department of Echocardiography, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai Institute of Medical Imaging

DOI: https://doi.org/10.1038/s41419-022-05100-4
Journal volume & issue: Vol. 13, no. 7
pp. 1 – 15

Abstract

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Abstract Doxorubicin (DOX)-based chemotherapy is widely used to treat malignant tumors; however, the cardiotoxicity induced by DOX restricts its clinical usage. A therapeutic dose of DOX can activate ubiquitin-proteasome system. However, whether and how ubiquitin-proteasome system brings out DOX-induced cardiotoxicity remains to be investigated. Here we conducted a proteomics analysis of a DOX-induced cardiotoxicity model to screen the potentially ubiquitination-related molecules. Dysregulated TRIM25 was found to contribute to the cardiotoxicity. In vivo and in vitro cardiotoxicity experiments revealed that TRIM25 ameliorated DOX-induced cardiotoxicity. Electron microscopy and endoplasmic reticulum stress markers revealed that TRIM25 mitigated endoplasmic reticulum stress and apoptosis in DOX-induced cardiomyocytes. Mechanistically, the Co-immunoprecipitation assays and CHX pulse-chase experiment determined that TRIM25 affected p85α stability and promoted its ubiquitination and degradation. This leads to increase of nuclear translocation of XBP-1s, which mitigates endoplasmic reticulum stress. These findings reveal that TRIM25 may have a therapeutic role for DOX-induced cardiotoxicity.

Published in Cell Death and Disease

ISSN: 2041-4889 (Online)
Publisher: Nature Publishing Group
Country of publisher: United Kingdom
LCC subjects: Science: Biology (General): Cytology
Website: http://www.nature.com/cddis/index.html

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