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.
Highlights
Mechanistic target of rapamycin complex 1 integrates various environmental signals to regulate cell growth and metabolism
To uncover the mechanism by which mechanistic target of rapamycin complex 1 (mTORC1) is inactivated under long-term amino acid treatment, we examined the
We found that ovarian tumor (OTU) domain– containing ubiquitin aldehyde-binding protein 1 (OTUB1) directly interacts with DEPTOR in cells and in vitro, resulting in stabilization of DEPTOR
Summary
OTUB1 is a potential DUB of DEPTOR mTORC1 signaling is activated by short-term amino acid treatment [44]. We were interested in studying whether and how mTORC1 activation is shut off by long-term amino acid treatment. Consistent with a previous study, treatment with amino acids results in mTORC1 activation in 1 h as determined by pS6K and pS6 [44]. We found that under longterm amino acid stimulation up to 6 h, the activation of mTORC1 signaling was significantly decreased (Fig. 1A), suggesting that a negative feedback might be operating to control such amino acid– dependent mTORC1 signaling pathway. To uncover the mechanism by which mTORC1 is inactivated under long-term amino acid treatment, we examined the
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