Mammalian target of rapamycin complex 1 (mTORC1) and mTORC2 both contain, and are inhibited by, DEP domain-containing mTOR-interacting protein (DEPTOR). Upon serum stimulation, DEPTOR is degraded by the 26S proteasome to allow mTOR activation, but the ubiquitin E3 ligase driving this degradation was unknown. Three groups now report that, following its phosphorylation by specific kinases, DEPTOR is targeted for degradation by the Skp1–cullin 1–F box–βTrCP (SCFβTrCP) E3 ubiquitin ligase.
The authors of these papers all sought to identify the E3 ligase that triggers DEPTOR degradation. Gao et al. overexpressed DEPTOR in cells and, using mass spectrometry, identified the F box protein β-transducin repeat-containing protein 2 (βTrCP2) as a DEPTOR-interacting protein. Zhao et al. examined DEPTOR for consensus binding motifs of F box proteins and identified βTrCP1 and βTrCP2 (which are thought to function redundantly) as DEPTOR-interacting proteins. Duan et al. screened a library of F box proteins, revealing that DEPTOR interacts with βTrCP1 and βTrCP2. Thus, SCFβTrCP is a candidate E3 ligase for DEPTOR. Indeed, further experiments by these groups confirmed that βTrCP induces DEPTOR degradation, and that DEPTOR must be phosphorylated within its degradation motif (known as a degron; 286-SSGYFS-291) to recruit βTrCP.
βTrCP induces DEPTOR degradation, and ... DEPTOR must be phosphorylated ... to recruit βTrCP.
But what kinases are required for DEPTOR degradation? Gao et al. and Duan et al. found that inhibitors of mTOR (the common active component of each mTORC) and casein kinase 1 (CK1) blocked βTrCP–DEPTOR interactions, degron phosphorylation and DEPTOR degradation. Furthermore, both groups found that mTOR induces initial 'priming' phosphorylations outside the DEPTOR degron, at Ser293 and Ser299, which is followed by CK1α-induced phosphorylation of degron Ser residues and subsequent βTrCP recruitment. Zhao et al. found that S6 kinase 1 (S6K1), a downstream target of mTOR signalling, and ribosomal S6K1 (RSK1) phosphorylate DEPTOR to enhance its βTrCP-mediated degradation; S6K1 seems to induce a priming phosphorylation for DEPTOR-targeted RSK1 activity. All of these results suggest that mTOR positively regulates its own activity by inducing the degradation of one of its key endogenous inhibitors, either directly or through its downstream target S6K1.
Finally, Zhao et al. and Gao et al. investigated how DEPTOR levels influence the ability of mTOR signalling to negatively regulate autophagy. Both groups found that glucose deprivation, which can trigger autophagy, increased DEPTOR protein levels, decreased mTORC1 activity and induced autophagy. Consistent with this, depletion of DEPTOR reduced autophagy induced by glucose limitation. Gao et al. also showed that an increase in DEPTOR, owing to βTrCP depletion, resulted in autophagy even in the presence of glucose. Interestingly, data from both groups also suggested that decreased mTORC1 activity, as a result of an increase in DEPTOR, might contribute to the chemotherapeutic resistance of cancer cells.
Together, these three papers reveal that mTOR signalling primes DEPTOR for phosphorylation by additional kinases, enabling SCFβTrCP to bind and trigger its degradation. Thus, mTOR can positively regulate its own activity to influence key biological responses, such as autophagy.
ORIGINAL RESEARCH PAPERS
Gao, D. et al. mTOR drives its own activation via SCFβTrCP-dependent degradation of the mTOR inhibitor DEPTOR. Mol. Cell 44, 290–303 (2011) Article
Zhao, Y., Xiong, X. & Sun, Y. DEPTOR, an mTOR inhibitor, is a physiological substrate of SCFβTrCP E3 ubiquitin ligase and regulates survival and autophagy. Mol. Cell 44, 304–316 (2011) Article
Duan, S. et al. mTOR generates an auto-amplification loop by triggering the βTrCP- and CK1α-dependent degradation of DEPTOR. Mol. Cell 44, 317–324 (2011) Article
Zoncu, R., Efeyan, A. & Sabatini, D. M. mTOR: from growth signal integration to cancer, diabetes and ageing. Nature Rev. Mol. Cell Biol. 12, 21–35 (2011)
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Wrighton, K. mTOR targets its own inhibitor. Nat Rev Mol Cell Biol 12, 769 (2011). https://doi.org/10.1038/nrm3229