3 years ago

OTUB1 suppresses mTOR complex 1 (mTORC1) activity by deubiquitinating the mTORC1 inhibitor DEPTOR.

Chenchen Jiao, Lu Deng, Yue Yu, Lei Chen, Linlin Zhao, Ping Wang, Xiao Tan, Xin Ge, Guoli Gao, Xiaoping Peng, Xinbo Wang, Weijuan Pan
Mechanistic target of rapamycin mTOR complex I (mTORC1) integrates various environmental signals to regulate cell growth and metabolism. DEPTOR, also termed DEPDC6, is an endogenous inhibitor of the mTORC1 and mTORC2 activities. The abundance of DEPTOR centrally orchestrates the mTOR signaling network. However, the mechanisms by which the DEPTOR stability is regulated are still elusive. Here, we report that OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) specifically deubiquitinates DEPTOR by a deubiquitination assay. We found that OTUB1 directly interacted with DEPTOR via its N-terminal domain and 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.

Publisher URL: http://doi.org/10.1074/jbc.M117.809533

DOI: 10.1074/jbc.M117.809533

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