泛素连接酶
生物
mTORC1型
泛素
脱氮酶
DNA连接酶
亮氨酸
营养感应
细胞生物学
生物化学
PI3K/AKT/mTOR通路
突变
氨基酸
癌症研究
信号转导
基因
作者
Dong Wang,Chenchen Xu,Wenyu Yang,Jie Chen,Yuhui Ou,Yuanyuan Guan,Jialiang Guan,Ying Liu
出处
期刊:Molecular Cell
[Elsevier]
日期:2022-02-01
卷期号:82 (4): 770-784.e9
被引量:38
标识
DOI:10.1016/j.molcel.2022.01.002
摘要
The mTOR complex 1 (mTORC1) is an essential metabolic hub that coordinates cellular metabolism with the availability of nutrients, including amino acids. Sestrin2 has been identified as a cytosolic leucine sensor that transmits leucine status signals to mTORC1. In this study, we identify an E3 ubiquitin ligase RING finger protein 167 (RNF167) and a deubiquitinase STAMBPL1 that function in concert to control the polyubiquitination level of Sestrin2 in response to leucine availability. Ubiquitination of Sestrin2 promotes its interaction with GATOR2 and inhibits mTORC1 signaling. Bioinformatic analysis reveals decreased RNF167 expression and increased STAMBPL1 expression in gastric and colorectal tumors. Knockout of STAMBPL1 or correction of the heterozygous STAMBPL1 mutation in a human colon cancer cell line suppresses xenograft tumor growth. Lastly, a cell-permeable peptide that blocks the STAMBPL1-Sestrin2 interaction inhibits mTORC1 and provides a potential option for cancer therapy.
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