Walther Flemming Award:
The TSC/mTOR signaling axis in nutrient sensing and the cellular stress response

Constantinos Demetriades

Max Planck Institute for Biology of Ageing (MPI-AGE), 50931 Cologne, Germany and CECAD, University of Cologne, 50931 Cologne, Germany

https://www.age.mpg.de/science/research-laboratories/demetriades/

The mTOR complex 1 (mTORC1) is a master regulator of cellular physiology and the main sensor of virtually all intra- and extra-cellular stimuli, including nutrient availability. The lysosomal surface is a cellular compartment where mTORC1 is recruited and activated when nutrients are abundant, whereas mTOR delocalizes away from lysosomes in response to amino acid scarcity.

In the context of my Walther Flemming Award talk, I will give a brief overview of my work suggesting that mTORC1 inactivation is not just the passive result due to the absence of positive stimuli, but rather regulated in an active manner. Amino acid removal inactivates mTORC1 via the lysosomal relocalization of the Tuberous Sclerosis Complex (TSC). The TSC recruitment to the lysosomal surface is necessary for proper mTORC1 delocalization, proper mTORC1 inactivation, and the cellular response to amino acid starvation. TSC-mutant cells show aberrantly hyperactive mTORC1 even under starvation conditions and therefore die due to a metabolic imbalance between nutritional demand and supply. Strikingly, TSC relocalization is not restricted to AA starvation, but is a universal response to cellular stress: each individual stress, when applied singly to cells, is sufficient to cause TSC accumulation to the lysosomal surface, thereby inhibiting mTORC1.

In sum, I will describe the mechanistic details of mTOR inactivation in response to nutrient starvation and will present a model explaining how information from multiple, diverse, cellular stresses is integrated to control cellular physiology.

 

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