LXJ
(2022-09-30 19:06):
#paper DOI:10.1016/j.molcel.2022.01.002. E3 ligase RNF167 and deubiquitinase STAMBPL1 modulate mTOR and cancer progression. mTOR复合物1（mTORC1）是一个重要的代谢中枢，可以将细胞代谢与营养物质（包括氨基酸）的可用性相协调。Sestrin2已被鉴定为一种细胞溶质亮氨酸传感器，可将亮氨酸状态信号传输至mTORC1。在本研究中，作者鉴定了一种E3泛素连接酶环指蛋白167（RNF167）和一种双歧化酶STAMBPL1，二者协同作用，控制Sestrin1的多泛素化水平，以响应亮氨酸的可用性。Sestrin2的泛素化促进其与GATOR2的相互作用并抑制mTORC1信号。生物信息学分析显示胃和结肠肿瘤中RNF167表达降低，STAMBPL1表达增加。在人类结肠癌细胞系中敲除STAMBPL1或纠正杂合STAMBPL 1突变可抑制异种移植瘤的生长。通过上述研究，作者旨在阐述一种阻断STAMBPL1-Sestrin2相互作用的细胞渗透性肽抑制mTORC1，为癌症治疗提供了潜在的选择。
E3 ligase RNF167 and deubiquitinase STAMBPL1 modulate mTOR and cancer progression
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Abstract:
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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