KLHL22 Promotes MTORC1 Activation and Breast Tumorigenesis

The mechanistic target of rapamycin complex 1 (mTORC1) is frequently deregulated in cancer and integrates environmental cues, such as amino acids, to regulate cell growth. mTORC1 is activated by RAG GTPases in response to amino acids and is inactivated under amino acid–deficient conditions by GATOR1 complex–mediated suppression of RAG GTPases. The GATOR1 complex is comprised of the subunits DEPDC5, NPRL3, and NPRL2, but the mechanism by which the inhibitory function of GATOR1 is relieved by amino-acid stimulation has not been determined. To determine how GATOR1-mediated mTORC1 inhibition is relieved during mTORC1 activation, Chen and colleagues investigated the stability of GATOR subunits during amino-acid starvation. Only the protein levels of the DEPDC5 subunit were dependent on amino-acid availability, with increasing expression during amino-acid starvation, whereas its mRNA levels were unchanged. Under basal conditions, treatment with a proteasome inhibitor resulted in DEPDC5 accumulation, suggesting that it is degraded by the proteasome in response to amino acids. Mechanistically, in response to amino acids, DEPDC5 degradation was induced by K48-linked polyubiquitination of DEPDC5 by the CUL3-KLHL22 E3 ubiquitin ligase. Thus, KLHL22 was required for mTORC1 activation, promoting downstream signaling, autophagy, and cell growth, and high-level KLHL22 expression increased sensitivity to mTORC1 inhibition. In patients with breast cancer, KLHL22 was upregulated in tumors compared with adjacent normal tissues, and KLHL22 upregulation was associated with reduced DEPDC5 levels. In breast cancer xenografts, KLHL22 depletion or mTORC1 inhibition suppressed tumor growth, indicating that KLHL22 may be an oncogene in breast cancer, activating mTORC1 signaling to promote tumor growth. Altogether, these findings elucidate a mechanism by which amino-acid activation relieves GATOR1-mediated mTORC1 inhibition and suggest the potential for therapeutic targeting of KLHL22 in breast cancer.

Chen J, Ou Y, Yang Y, Li W, Xu Y, Xie Y, et al. KLHL22 activates amino-acid-dependent mTORC1 signalling to promote tumorigenesis and ageing. Nature 2018;557:585–9.

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