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Disruption of the Rag-Ragulator Complex by c17orf59 Inhibits mTORC1
Lawrence D Schweitzer1, William C Comb1, Liron Bar-Peled1
1Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, MIT, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA; Broad Institute, Cambridge, MA 02142, USA; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA.
Abstract:
mTORC1 controls key processes that regulate cell growth, including mRNA translation, ribosome biogenesis, and autophagy. Environmental amino acids activate mTORC1 by promoting its recruitment to the cytosolic surface of the lysosome, where its kinase is activated downstream of growth factor signaling. mTORC1 is brought to the lysosome by the Rag GTPases, which are tethered to the lysosomal membrane by Ragulator, a lysosome-bound scaffold. Here, we identify c17orf59 as a Ragulator-interacting protein that regulates mTORC1 activity through its interaction with Ragulator at the lysosome. The binding of c17orf59 to Ragulator prevents Ragulator interaction with the Rag GTPases, both in cells and in vitro, and decreases Rag GTPase lysosomal localization. Disruption of the Rag-Ragulator interaction by c17orf59 impairs mTORC1 activation by amino acids by preventing mTOR from reaching the lysosome. By disrupting the Rag-Ragulator interaction to inhibit mTORC1, c17orf59 expression may represent another mechanism to modulate nutrient sensing by mTORC1.
Insights
A newly identified protein, c17orf59, regulates cell growth by inhibiting mTORC1 activation. It disrupts the Rag-Ragulator interaction, preventing mTORC1 from localizing to the lysosome in response to amino acids.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth, controlling processes like mRNA translation, ribosome biogenesis, and autophagy.
- Amino acid availability activates mTORC1 via its recruitment to the lysosome, a process mediated by Rag GTPases and the Ragulator scaffold.
Purpose of the Study:
- To identify novel regulators of mTORC1 localization and activity at the lysosome.
- To elucidate the mechanism by which c17orf59 modulates mTORC1 signaling in response to nutrients.
Main Methods:
- Co-immunoprecipitation assays to assess protein-protein interactions (c17orf59, Ragulator, Rag GTPases).
- Cell-based assays to determine lysosomal localization of Rag GTPases and mTORC1.
- In vitro binding assays to confirm direct interactions.
Main Results:
- c17orf59 directly binds to the Ragulator complex on the lysosome.
- This interaction prevents Rag GTPases from binding to Ragulator, reducing their lysosomal localization.
- Disruption of the Rag-Ragulator-mTORC1 axis by c17orf59 impairs amino acid-induced mTORC1 activation.
Conclusions:
- c17orf59 acts as an inhibitor of mTORC1 signaling by interfering with the Rag GTPase-Ragulator interaction at the lysosome.
- This finding reveals a new mechanism for modulating nutrient sensing pathways, impacting cell growth regulation.
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