Fig. 3

Lysosome as the nutrient sensor and signaling hub of the cell. Emerging evidence indicates that the lysosome in addition to performing its digestive function also acts as a signaling hub for regulating cellular metabolism. In growing cells, signals from amino acids (e.g. arginine, leucine etc), within the lysosomal lumen are integrated upstream of the Rag and Rheb GTPases to promote recruitment of mTORC1 on lysosomal membrane leading to its activation. Signals from other factors such as oxygen and growth factors are also integrated in this fashion by the AKT-TSC pathway. Upon activation, AKT relieves the TSC complex from inhibiting Rheb. The v-ATPase, Ragulator, Rag GTPases and SLC38A9 also participate in the complex process of mTORC1-translocation to the lysosomal membrane where it is activated. Disruption of one or more of these signaling inputs may impair mTORC1 signaling and its recruitment to the lysosomal membrane suppressing its kinase activity. It should be noted that in a nutrient replete state the mTORC1 activation stimulates cell proliferation (anabolic effect), whereas in nutrient depleted state mTORC1 is inactive allowing autophagic pathway to be active (catabolic effect). Most notably, inhibition of mTORC1 by rapamycin and its analogs has been reported to ameliorate pathology and increase lifespan. Abbreviations used: mTORC1, mechanistic target of rapamycin complex 1; AKT, Protein kinase B; TSC, Tuberous sclerosis complex; IGFR, Insulin-like growth factor receptor