2. Academic Validation
  3. E3 ligase RNF167 and deubiquitinase STAMBPL1 modulate mTOR and cancer progression

E3 ligase RNF167 and deubiquitinase STAMBPL1 modulate mTOR and cancer progression

  • Mol Cell. 2022 Feb 17;82(4):770-784.e9. doi: 10.1016/j.molcel.2022.01.002.
Dong Wang 1,  Chenchen Xu 1,  Wenyu Yang 2,  Jie Chen 1,  Yuhui Ou 1,  Yuanyuan Guan 1,  Jialiang Guan 3,  Ying Liu 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China.
  • 2 Yuan Pei College, Peking University, Beijing 100871, China.
  • 3 PKU-Tsinghua-NIBS Graduate Program, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
  • 4 State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Beijing Advanced Innovation Center for Genomics, Beijing 100871, China. Electronic address: [email protected].
PMID: 35114100 DOI: 10.1016/j.molcel.2022.01.002
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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