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OTUB1 protein suppresses mTOR complex 1 (mTORC1) activity by deubiquitinating the mTORC1 inhibitor DEPTOR
- Source :
- Journal of Biological Chemistry. 293:4883-4892
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates various environmental signals to regulate cell growth and metabolism. DEPTOR, also termed DEPDC6, is an endogenous inhibitor of mTORC1 and mTORC2 activities. The abundance of DEPTOR centrally orchestrates the mTOR signaling network. However, the mechanisms by which DEPTOR stability is regulated are still elusive. Here, we report that OTU domain–containing ubiquitin aldehyde-binding protein 1 (OTUB1) specifically deubiquitinates DEPTOR in a deubiquitination assay. We found that OTUB1 directly interacted with DEPTOR via its N-terminal domain, deubiquitinated DEPTOR, and thereby stabilized DEPTOR in a Cys-91–independent but Asp-88–dependent manner, suggesting that OTUB1 targets DEPTOR for deubiquitination via a deubiquitinase activity–independent non-canonical mechanism. The interaction between OTUB1 and DEPTOR was enhanced when the cells were treated with amino acids. Moreover, OTUB1 suppressed amino acid–induced activation of mTORC1 in a DEPTOR-dependent manner and thereby ultimately controlled cellular autophagy, cell proliferation, and size. Our findings reveal a mechanism that stabilizes the mTORC1 inhibitor DEPTOR via OTUB1's deubiquitinase activity. Our insights may inform research into various mTOR activity–related diseases, such as cancer, and may contribute to the identification of new diagnostic markers and therapeutic strategies for cancer treatments.
- Subjects :
- 0301 basic medicine
mTORC1
Mechanistic Target of Rapamycin Complex 1
DEPTOR
Biochemistry
mTORC2
Deubiquitinating enzyme
03 medical and health sciences
0302 clinical medicine
Protein Domains
Autophagy
Humans
Molecular Biology
Mechanistic target of rapamycin
PI3K/AKT/mTOR pathway
Cell Proliferation
Deubiquitinating Enzymes
biology
Protein Stability
Chemistry
Intracellular Signaling Peptides and Proteins
Ubiquitination
Cell Biology
Cell biology
Cysteine Endopeptidases
030104 developmental biology
OTUB1
030220 oncology & carcinogenesis
biology.protein
HeLa Cells
Deubiquitination
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 293
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....f6cdbf2f3dc8da24683998f204b73685