Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes
What this study shows
The authors asked how TFEB reaches the lysosome, where mTORC1 phosphorylates it. In human cells, depleting Raptor inactivated mTORC1 and sent TFEB to the nucleus but did not stop TFEB binding lysosomes (82.5% of cells still showed lysosomal TFEB), whereas depleting the Rag GTPases or the Ragulator subunit p18 abolished it (under 4% of Rag-depleted cells kept the S211A mutant on lysosomes, against about 80% of controls). TFEB bound only active Rag heterodimers through its first 30 amino acids, and active Rags were enough to bring TFEB to lysosomes; TFEB mutants that could not bind Rags lost S211 phosphorylation and stayed in the nucleus. Endogenous TFEB accumulated in the nucleus after Torin1 or amino-acid starvation and moved back to the cytosol and lysosomes when amino acids were added again. Some MITF isoforms behaved the same way. Boundary: Human cell lines, mostly with overexpressed or mutant proteins; not tested in tissues or whole animals.
At a glance
| Evidence type | M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Human ARPE-19, HeLa, HEK-293T cells; siRNA against Raptor, RagA/B, RagC/D, p18 (LAMTOR1); active/inactive Rag mutants; TFEB and MITF deletion/point mutants; Torin1 and amino-acid starvation) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is. |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Human ARPE-19, HeLa, HEK-293T cells; siRNA against Raptor, RagA/B, RagC/D, p18 (LAMTOR1); active/inactive Rag mutants; TFEB and MITF deletion/point mutants; Torin1 and amino-acid starvation |
| Journal | Journal of Cell Biology |
| Year | 2013 |
| Peer reviewed | Yes |
| Record last updated | 2026-10-01 |
| Source | DOI 10.1083/jcb.201209135 · PMID 23401004 · Free full text (PMC3575543) |
Extracted findings
These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.
| Intervention | siRNA depletion of Raptor, Rags or p18; active/inactive Rag mutants; Torin1; amino-acid starvation and re-feeding; TFEB N-terminal mutants |
| Target | Rag GTPases -> TFEB lysosomal recruitment -> mTORC1-dependent TFEB phosphorylation |
| Model | Human cells |
| Effect | Active Rags recruited TFEB to lysosomes, which was needed for mTORC1-dependent TFEB phosphorylation and cytosolic retention; mTORC1 inhibition sent TFEB to the nucleus |
In the Atlas
Related topics
Links in the pathway map
- Supports mTORC1 inhibits TFEB
More studies on this topic
- Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes (2017)
- NUFIP1 is a ribosome receptor for starvation-induced ribophagy (2018)
- mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin (2013)
- ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase (2013)
Thank you. Your answer was counted anonymously.