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. 2022 Feb 17;82(4):770-784.e9.
doi: 10.1016/j.molcel.2022.01.002. Epub 2022 Feb 2.

E3 ligase RNF167 and deubiquitinase STAMBPL1 modulate mTOR and cancer progression

Dong Wang  1 , Chenchen Xu  1 , Wenyu Yang  2 , Jie Chen  1 , Yuhui Ou  1 , Yuanyuan Guan  1 , Jialiang Guan  3 , Ying Liu  4
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Free article

E3 ligase RNF167 and deubiquitinase STAMBPL1 modulate mTOR and cancer progression

Dong Wang et al. Mol Cell. .
Free article

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.

Keywords: Sestrin2; amino acid sensing; colorectal cancer; mTOR; tumorigenesis; ubiquitination.

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Conflict of interest statement

Declaration of interests Y.L., D.W., C.X., W.Y., and Y.G. are named inventors of pending patent applications (202110704816.2 to the Chinese Patent Office) related to the work. The authors declare no competing interests.

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