Spatio-temporal association between mTOR and autophagy during cellular senescence.

Abstract:: Evidence for a connection between lysosomes and mTOR is emerging. Seminal work from the Sabatini laboratory has shown that mTOR can be recruited to the lysosomal surface in response to amino acids, in a Rag GTPase-dependent manner, to become activated by Rheb. However the biological significance of this is not fully understood. Recent work from our laboratory has shown that lysosomes spatially link mTOR and autophagy forming a cytoplasmic compartment in close proximity to the Golgi apparatus (GA) during oncogenic Ras-induced senescence. The TOR-autophagy spatial coupling compartment (TASCC) is enriched for autolysosomes, but largely excludes autophagosomes. Our data suggest that mTOR, which is a positive regulator of protein synthesis, is recruited, in part, by the amino acid-rich environment surrounding the autolysosomes. This then facilitates protein synthesis at the nearby rER-GA system, reinforcing lysosome and autophagy biogenesis. Proper TASCC formation contributes to the production of secretory proteins, which also utilizes the rER-GA system. Since mTOR inhibits autophagy during the initial stages of autophagosome formation, TASCC formation is likely to facilitate autophagy by sequestering mTOR, suggesting that the TASCC is a self-enhancing structure.

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