SZT2 dictates GATOR control of mTORC1 signalling

Mechanistic target of rapamycin complex 1 (TORC1) integrates nutrient signals to control cell growth and organismal homeostasis across eukaryotes(1-4). The evolutionarily conserved GATOR complex regulates mTORC1 signalling through Rag GTPases, and GATOR1 displays GTPase activating protein (GAP) activity for RAGA and RAGB (RAGA/B) and GATOR2 has been proposed to be an inhibitor of GATOR1(5,6). Furthermore, the metazoan-specific SESN proteins function as guanine nucleotide dissociation inhibitors (GDIs) for RAGA/B, and interact with GATOR2 with unknown effects(7-9). Here we show that SZT2 (seizure threshold 2), a metazoan-specific protein mutated in epilepsy(10-13), recruits a fraction of mammalian GATOR1 and GATOR2 to form a SZT2-orchestrated GATOR (SOG) complex with an essential role in GATOR-and SESN-dependent nutrient sensing and mTORC1 regulation. The interaction of SZT2 with GATOR1 and GATOR2 was synergistic, and an intact SOG complex was required for its localization at the lysosome. SZT2 deficiency resulted in constitutive mTORC1 signalling in cells under nutrient-deprived conditions and neonatal lethality in mice, which was associated with failure to inactivate mTORC1 during fasting. Hyperactivation of mTORC1 in SZT2-deficient cells could be partially corrected by overexpression of the GATOR1 component DEPDC5, and by the lysosome-targeted GATOR2 component WDR59 or lysosome-targeted SESN2. These findings demonstrate that SZT2 has a central role in dictating GATOR-dependent nutrient sensing by promoting lysosomal localization of SOG, and reveal an unexpected function of lysosome-located GATOR2 in suppressing mTORC1 signalling through SESN recruitment.