交通2
信号转导衔接蛋白
mTORC1型
泛素连接酶
癌症研究
生物
细胞生物学
基因敲除
免疫沉淀
泛素
癌变
癌细胞
信号转导
肿瘤坏死因子α
癌症
细胞培养
PI3K/AKT/mTOR通路
免疫学
生物化学
遗传学
基因
肿瘤坏死因子受体
作者
Xue Liang,Jiping Yao,Danrui Cui,Weiyang Zheng,Yanning Liu,Guohua Lou,Bingjue Ye,Liyan Shui,Yi Sun,Yongchao Zhao,Min Zheng
标识
DOI:10.1038/s41418-023-01164-7
摘要
TRAF2 (Tumor necrosis factor receptor-associated factor 2) is a dual function protein, acting as an adaptor protein and a ubiquitin E3 ligase, which plays an essential role in mediating the TNFα-NFκB signal pathway. Dysregulated expression of TRAF2 has been reported in a variety of human cancers. Whether and how TRAF2 regulates the growth of liver cancer cells remains elusive. The goal of this study is to investigate potential dysregulation of TRAF2 and its biological function in liver cancer, and to elucidate the underlying mechanism, leading to validation of TRAF2 as an attractive liver cancer target. Here, we reported TRAF2 is up-regulated in human liver cancer cell lines and tissues, and high TRAF2 expression is associated with a poor prognosis of HCC patients. Proteomics profiling along with Co-immunoprecipitation analysis revealed that p62 is a new substrate of TRAF2, which is subjected to TRAF2-induced polyubiquitination via the K63 linkage at the K420 residue. A strong negative correlation was found between the protein levels of p62 and TRAF2 in human HCC samples. TRAF2 depletion inhibited growth and survival of liver cancer cells both in vitro and in vivo by causing p62 accumulation, which is partially rescued by simultaneous p62 knockdown. Mechanistically, TRAF2-mediated p62 polyubiquitylation activates the mTORC1 by forming the p62-mTORC1-Rag complex, which facilitates the lysosome localization of mTORC1. TRAF2 depletion inhibited mTORC1 activity through the disruption of interaction between p62 and the mTORC1 complex. In conclusion, our study provides the proof-of-concept evidence that TRAF2 is a valid target for liver cancer.
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