DEPTOR, an mTOR inhibitor, is a physiological substrate of SCF(ßTrCP) E3 ubiquitin ligase and regulates survival and autophagy.

DEPTOR, an inhibitor of mTORC1 and mTORC2, is degraded via ubiquitin-proteasome pathway by an unknown E3 ubiquitin ligase. Here we report that DEPTOR is a physiological substrate of SCF(ßTrCP) E3 ligase for targeted degradation. Upon growth factor stimulation, RSK1 and S6K1 kinases are activated to phosphorylate DEPTOR, which is then recognized by the F box protein, ßTrCP, via its degron sequence for subsequent ubiquitination and degradation by SCF E3. Endogenous DEPTOR levels are negatively regulated by ßTrCP. DEPTOR half-life is shortened by ßTrCP but extended by a dominant-negative mutant of ßTrCP, by RSK1/S6K1 inhibition, and by ßTrCP degron site mutations. Biologically, DEPTOR accumulation upon ßTrCP knockdown inactivates mTORC1 and activates AKT in cancer cells to confer resistance to rapamycin and paclitaxel. Furthermore, DEPTOR accumulates upon glucose deprivation and mTOR inhibition to induce autophagy. Thus, ßTrCP-DEPTOR-mTOR intertwine to regulate cell survival and autophagy.