期刊
NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-019-14190-2
关键词
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资金
- National Natural Science Foundation of China [31801186, 31701005, 81572832, 81874174]
- Shenzhen Basic Science Research Project [JCYJ20170413153158716]
- SIAT Innovation Program for Excellent Young Researchers [201801]
- Shanghai Rising-Star Program [18QA1402600]
- Shanghai Municipal Commission of Health and Family Planning [2018YQ12]
- School of Medicine, Shanghai Jiao Tong University [17XJ11015, 18XJ11006]
- National Institutes of Health [R01CA182675, R01CA184867]
- Wealth Strategy Holding Limited
- SIAT-GHMSC Biomedical Laboratory for Major Human Diseases
Tumor cells often exhibit augmented capacity to maintain endoplasmic reticulum (ER) homeostasis under adverse conditions, yet the underlying mechanisms are not well defined. Here, through the evaluation of all human TRIM proteins, we find that TRIM25 is significantly induced upon ER stress. Upregulation of TRIM25 ameliorates oxidative stress, promotes ER-associated degradation (ERAD), and reduces IRE1 signaling in the UPR pathway. In contrast, depletion of TRIM25 leads to ER stress and attenuates tumor cell growth in vitro and in vivo. Mechanistically, TRIM25 directly targets Keap1 by ubiquitination and degradation. This leads to Nrf2 activation, which bolsters anti-oxidant defense and cell survival. TRIM25 expression is positively associated with Nrf2 expression and negatively with Keap1 expression in hepatocellular carcinoma (HCC) xenografts and specimens. Moreover, high TRIM25 expression correlates with poor patient survival in HCC. These findings reveal TRIM25 as a regulator of ER homeostasis and a potential target for tumor therapy.
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