Extended Data Figure 10. SZT2-GATOR-Sestrin2 in nutrient sensing and mTORC1 signaling.

We propose that the SZT2-Orchestrated GATOR (SOG) complex sets a platform for nutrient sensing and mTORC1 regulation in metazoans. In this model, GATOR1 not only functions as a GAP that inactivates RagA and RagB (not depicted), but also recruits GATOR2 to the lysosome via SZT2. Under nutrient deprivation conditions, Sestrin2 is further recruited to the lysosome, and represses RagA/B through its GDI activity. Upon nutrient stimulation, the GAP activity of GATOR1 may be repressed by GATOR2 via unknown mechanisms, while the leucine-bound Sestrin2 dissociates from GATOR2. In line with the general mode of GDI regulation, leucine could be considered as a GDI-dissociation factor (GDF) for Sestrin2. In SZT2-deficient cells, GATOR1, GATOR2 and likely Sestrin2 dissociate from the lysosome resulting in constitutive RagA/B activation and mTORC1 signaling, but the leucine-regulated Sestrin2 interaction with GATOR2 is not affected. AA, amino acids; Leu, leucine.