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PtdIns3P controls mTORC1 signaling through lysosomal positioning
Zhi Hong1,2, Nina Marie Pedersen1,2, Ling Wang1,2
1Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, Oslo, Norway.
The Journal of Cell Biology
|October 15, 2017
Summary
Amino acids activate the mechanistic target of rapamycin complex 1 (mTORC1) by promoting lysosome positioning. This lipid kinase-dependent process involves FYCO1 and Protrudin, linking nutrient sensing to mTORC1 signaling.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- The mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth and metabolism.
- mTORC1 activation is linked to lysosome positioning and lipid signaling, but the underlying mechanisms are unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms connecting lysosome positioning and mTORC1 activation.
- To investigate the roles of FYCO1 and Protrudin in mTORC1 signaling.
Main Methods:
- Overexpression and depletion of Protrudin and FYCO1.
- Analysis of lysosome localization and mTORC1 activity.
- Investigating phosphatidylinositol 3-phosphate (PtdIns3P) binding.
Main Results:
- Amino acids promote FYCO1 recruitment to lysosomes and ER-lysosome contacts via Protrudin.
- Overexpression of Protrudin and FYCO1 drives peripheral lysosome translocation and mTORC1 activation.
- VPS34 inhibition or depletion of Protrudin/FYCO1 causes perinuclear lysosome clustering and reduced mTORC1 activity.
Conclusions:
- Phosphatidylinositol 3-phosphate (PtdIns3P)-dependent lysosome translocation to the cell periphery is a key mechanism for promoting mTORC1 activation.
- This pathway integrates nutrient availability with cellular anabolic processes.