Impaired lysosome function can induce autophagy via suppression of mTOR activity (738.1)

Autophagy is an evolutionarily conserved mechanism by which cytoplasmic material is degraded in the lysosomal compartment to fuel starving cells and eliminates intracellular pathogens. Autophagy can be activated via MTORC1 downregulation by amino acid deprivation and by certain chemicals. Lysosome is the degrading machine for autophagy, but has also been linked to MTORC1 activation through the Rag GTPase pathway. In this study, classical lysosome inhibitors, such as chloroquine, E64d and pepstatin A, were found to be able to inhibit mTORC1 in a Rag‐dependent manner. All these lysosome inhibitors were able to activate events associated with early autophagy biogenesis represented by ATG16L1 and ATG12 puncta formation, indicating a consequence of autophagy activation following MTORC1 suppression. Our data suggested a general link from lysosome function to the Rag‐MTORC1 signaling axis and autophagy activation. Thus the lysosome is not only required for autophagic degradation, but also affects autophagy activation. Lysosomal inhibitors can have a dual effect in suppressing autophagy degradation and in initiating autophagy. Grant Funding Source : Supported by Guandong Provincial Natural Science Foundation, China (S2013010015876)