WAC Regulates mTOR Activity by Acting as an Adaptor for the TTT and Pontin/Reptin Complexes

The ability to sense energy status is crucial in the regulation of metabolism via the mechanistic Target of Rapamycin Complex 1 (mTORC1). The assembly of the TTT-Pontin/Reptin complex is responsive to changes in energy status. Under energy-sufficient conditions, the TTT-Pontin/Reptin complex promotes mTORC1 dimerization and mTORC1-Rag interaction, which are critical for mTORC1 activation. We show that WAC is a regulator of energy-mediated mTORC1 activity. In a Drosophila screen designed to isolate mutations that cause neuronal dysfunction, we identified wacky, the homolog of WAC. Loss of Wacky leads to neurodegeneration, defective mTOR activity, and increased autophagy. Wacky and WAC have conserved physical interactions with mTOR and its regulators, including Pontin and Reptin, which bind to the TTT complex to regulate energy-dependent activation of mTORC1. WAC promotes the interaction between TTT and Pontin/Reptin in an energy-dependent manner, thereby promoting mTORC1 activity by facilitating mTORC1 dimerization and mTORC1-Rag interaction. The activity of the master metabolic regulator, mTOR, is tightly regulated to respond to environmental cues. David-Morrison, Xu, et al. identified the adaptor Wacky/WAC as a conserved modulator of mTOR activity. Wacky/WAC facilitates mTORC1 dimerization and Rag association through a chaperone complex consisting of TTT and Pontin/Reptin.