KLHL22 activates amino-acid-dependent mTORC1 signalling to promote tumorigenesis and ageing

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that responds to a diverse set of environmental cues, including amino acids1,2. Deregulation of mTORC1 has been linked with metabolic diseases, cancer and ageing2–4. In response to amino acids, mTORC1 is recruited by the Rag GTPases to the lysosome, its site of activation5,6. The GATOR1 complex, consisting of DEPDC5, NPRL3 and NPRL2, displays GAP activity to inactivate Rag GTPases under amino-acid-deficient conditions 7 . However, it is unclear how the inhibitory function of GATOR1 is released upon amino acid stimulation. Here we find that in response to amino acids, the CUL3–KLHL22 E3 ubiquitin ligase promotes K48-linked polyubiquitination and degradation of DEPDC5, an essential subunit of GATOR1. KLHL22 plays a conserved role to mediate the activation of mTORC1 and downstream events in mammals and nematodes. Depletion of MEL-26, the Caenorhabditis elegans orthologue of KLHL22, extends worm lifespan. Moreover, KLHL22 levels are elevated in tumours of breast cancer patients, whereas DEPDC5 levels are correspondingly reduced. Depletion of KLHL22 in breast cancer cells suppresses tumour growth in nude mice. Therefore, pharmacological interventions targeting KLHL22 may have therapeutic potential for the treatment of breast cancer and age-related diseases. In response to amino acid stimulation, the ubiquitin E3 ligase CUL3–KLHL22 promotes the activation of mTORC1, which may drive tumour growth in breast cancer.