Amino acids recruit folliculin to lysosomes to support Rag-dependent mTORC1 activation.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Mammalian cells |
| Journal | The Journal of cell biology |
| Year | 2013 |
| Peer reviewed | Yes |
| Source | DOI 10.1083/jcb.201307084 · PMID 24081491 · Free full text (PMC3787382) |
Birt-Hogg-Dube syndrome, a human disease characterized by fibrofolliculomas (hair follicle tumors) as well as a strong predisposition toward the development of pneumothorax, pulmonary cysts, and renal carcinoma, arises from loss-of-function mutations in the folliculin (FLCN) gene. In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). Our results indicate that FLCN is specifically required for the amino acid-stimulated recruitment of mTORC1 to lysosomes by Rag GTPases. We further demonstrated that FLCN itself was selectively recruited to the surface of lysosomes after amino acid depletion and directly bound to RagA via its GTPase domain. FLCN-interacting protein 1 (FNIP1) promotes both the lysosome recruitment and Rag interactions of FLCN. These new findings define the lysosome as a site of action for FLCN and indicate a critical role for FLCN in the amino acid-dependent activation of mTOR via its direct interaction with the RagA/B GTPases.
| Intervention | Genetic/biochemical (FLCN) |
| Target | FLCN / Rag GTPases / mTORC1 |
| Model | Mammalian cells |
| Effect | Amino-acid-stimulated recruitment of folliculin (FLCN) to lysosomes supports Rag GTPase activation |