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mTORC1 activity licenses its own release from the lysosomal surface
Aishwarya Acharya1, Constantinos Demetriades2
1Max Planck Institute for Biology of Ageing (MPI-AGE), 50931 Cologne, Germany; Cologne Graduate School of Ageing Research (CGA), 50931 Cologne, Germany.
Molecular Cell
|November 1, 2024
Summary
mTORC1 activity is regulated by its location. Inhibiting mTORC1 traps it on lysosomes, preventing its release to regulate cellular functions and potentially avoiding futile cycling.
Area of Science:
- Cellular Biology
- Molecular Biology
- Biochemistry
Background:
- Nutrient signaling converges on the mechanistic target of rapamycin complex 1 (mTORC1), a key regulator of cellular physiology.
- mTORC1 activity is modulated by its dynamic localization between the lysosome and cytoplasm, influenced by Rag GTPases.
- The mechanisms governing mTORC1 release from lysosomes and the impact of its activity on localization are not fully understood.
Purpose of the Study:
- To investigate the relationship between mTORC1 activity, localization, and release from lysosomes.
- To elucidate the role of Rag GTPases in mTORC1 release.
- To understand how mTORC1 inhibition affects its subcellular positioning.
Main Methods:
- Utilized human cell lines.
- Manipulated mTORC1 activity through inhibition.
- Observed mTORC1 localization and phosphorylation of substrates like TFEB under various conditions, including starvation.
Main Results:
- mTORC1 inhibition prevented its release from lysosomes, even during starvation.
- Sustained phosphorylation of the lysosomal substrate TFEB was observed upon mTORC1 inhibition.
- "Inactive" mTORC1 led to persistent Rag GTPase activation, indicating active mediation of release.
Conclusions:
- mTORC1 controls its own lysosomal localization, with inhibition actively preventing its release.
- This mechanism likely prevents inefficient cycling of mTORC1 on and off the lysosome.
- Rag GTPases play a crucial role in mediating mTORC1 release from lysosomes.
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