Folliculin and its binding partners FNIP1/2; act as a GTPase-activating protein (GAP) for RagC/D, switching the Rag heterodimer into the configuration that recruits mTORC1 to the lysosome. FLCN-FNIP complements the GATOR1/GATOR2 arm by regulating the RagC/D half of the cycle. Loss of FLCN causes Birt-Hogg-Dube syndrome through a SUBSTRATE-SPECIFIC defect rather than blanket mTORC1 hyperactivation: canonical outputs (S6K1, 4E-BP1) are largely preserved, while TFEB and TFE3 escape phosphorylation and accumulate in the nucleus (NAP2020).
The switch that decides which substrates mTORC1 gets.
Folliculin is a *positive* regulator of the RagC/D arm despite being a tumour suppressor in Birt–Hogg–Dubé — the substrate-selective mTORC1 pathway explains the apparent contradiction.
| Tier | What it means | Studies |
|---|---|---|
| D | Mechanistic / in vitro / review | 3 |
No direct human evidence in the Atlas for this entity yet — everything below rests on animal or mechanistic work.
| Study | Year | Tier | Finding |
|---|---|---|---|
| ULL2026 | 2026 | D | In BHD patient-derived kidney cancer cells, FLCN loss causes constitutive nuclear TFEB localization and mTORC1 hyperactivation, but leaves bulk autophagy flux and LC3 lipidation unaffected; however, t |
| PET2013 | 2013 | D | Amino acids recruit folliculin to lysosomes to support Rag-dependent mTORC1 activation. |
| TSU2013 | 2013 | D | Folliculin is a GAP for RagC/D that signals amino-acid sufficiency, activating mTORC1 substrate binding. |