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A Ragulator-BORC interaction controls lysosome positioning in response to amino acid availability
Jing Pu1, Tal Keren-Kaplan1, Juan S Bonifacino2
1Cell Biology and Neurobiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
The Journal of Cell Biology
|October 11, 2017
Summary
Cellular amino acid levels control lysosome positioning. The Ragulator complex binds to BORC, a lysosome-dispersing factor, to regulate this process independently of mTORC1 signaling.
Area of Science:
- Cell Biology
- Molecular Biology
- Cellular Signaling
Background:
- Lysosomes are crucial for cellular responses to nutrient availability, particularly amino acids.
- Amino acid depletion activates a pathway involving Ragulator and Rag GTPases, inactivating mTORC1 and altering protein synthesis and autophagy.
- Lysosome clustering near the nucleus during amino acid starvation is observed, but the underlying mechanisms are unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms controlling lysosome positioning in response to amino acid availability.
- To investigate the role of the Ragulator complex and its interaction with other cellular components in lysosome redistribution.
Main Methods:
- Co-immunoprecipitation assays to detect protein-protein interactions.
- Cellular imaging techniques to observe lysosome localization.
- Biochemical assays to assess mTORC1 activity and substrate phosphorylation.
Main Results:
- Ragulator directly interacts with the BLOC-1-related complex (BORC), a known regulator of lysosome motility.
- This interaction negatively regulates BORC activity in an mTORC1-independent manner.
- Amino acid depletion enhances the Ragulator-BORC interaction, leading to lysosome clustering.
Conclusions:
- Amino acid availability regulates lysosome positioning through a novel mechanism involving the Ragulator complex.
- Ragulator modulates BORC activity, influencing lysosome distribution to the juxtanuclear region during nutrient scarcity.
- This pathway provides a direct link between cellular nutrient status and organelle positioning, independent of mTORC1 signaling.