PtdIns3P controls mTORC1 signaling through lysosomal positioning
| Autor: | Nina Pedersen, Maria Lyngaas Torgersen, Harald Stenmark, Ling Wang, Zhi Hong, Camilla Raiborg |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Vesicular Transport Proteins Retinal Pigment Epithelium mTORC1 Mechanistic Target of Rapamycin Complex 1 Biology Endoplasmic Reticulum Article 03 medical and health sciences Phosphatidylinositol Phosphates Cell Line Tumor Lysosome Autophagy medicine Humans ATG16L1 Research Articles Cell Nucleus Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Kinase Endoplasmic reticulum Biological Transport Epithelial Cells Cell Biology Class III Phosphatidylinositol 3-Kinases Cell biology DNA-Binding Proteins HEK293 Cells 030104 developmental biology medicine.anatomical_structure Gene Expression Regulation TFEB biological phenomena cell phenomena and immunity Signal transduction Lysosomes Microtubule-Associated Proteins HeLa Cells Signal Transduction Transcription Factors |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| Popis: | mTORC1 is activated by lysosome positioning and by amino acid–induced phosphatidylinositol 3-phosphate (PtdIns3P). Hong et al. show that amino acids stimulate recruitment of the PtdIns3P-binding protein FYCO1 to lysosomes and promote contacts between FYCO1 lysosomes and ER that contains the PtdIns3P effector Protrudin, mediating lysosome translocation and facilitating mTORC1 activation. The mechanistic target of rapamycin complex 1 (mTORC1) is a protein kinase complex that localizes to lysosomes to up-regulate anabolic processes and down-regulate autophagy. Although mTORC1 is known to be activated by lysosome positioning and by amino acid–stimulated production of phosphatidylinositol 3-phosphate (PtdIns3P) by the lipid kinase VPS34/PIK3C3, the mechanisms have been elusive. Here we present results that connect these seemingly unrelated pathways for mTORC1 activation. Amino acids stimulate recruitment of the PtdIns3P-binding protein FYCO1 to lysosomes and promote contacts between FYCO1 lysosomes and endoplasmic reticulum that contain the PtdIns3P effector Protrudin. Upon overexpression of Protrudin and FYCO1, mTORC1–positive lysosomes translocate to the cell periphery, thereby facilitating mTORC1 activation. This requires the ability of Protrudin to bind PtdIns3P. Conversely, upon VPS34 inhibition, or depletion of Protrudin or FYCO1, mTORC1-positive lysosomes cluster perinuclearly, accompanied by reduced mTORC1 activity under nutrient-rich conditions. Consequently, the transcription factor EB enters the nucleus, and autophagy is up-regulated. We conclude that PtdIns3P-dependent lysosome translocation to the cell periphery promotes mTORC1 activation. |
| Databáze: | OpenAIRE |
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