Folliculin - Q8NFG4 (FLCN_HUMAN)


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GTPase-activating protein that plays a key role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3 (PubMed:17028174, PubMed:18663353, PubMed:21209915, PubMed:24081491, PubMed:24095279, PubMed:31704029, PubMed:31672913). Activates mTORC1 by acting as a GTPase-activating protein: specifically stimulates GTP hydrolysis by RRAGC/RagC or RRAGD/RagD, promoting the conversion to the GDP-bound state of RRAGC/RagC or RRAGD/RagD, and thereby activating the kinase activity of mTORC1 (PubMed:24095279, PubMed:31704029, PubMed:31672913). The GTPase-activating activity is inhibited during starvation and activated in presence of nutrients (PubMed:31672913). Acts as a key component for mTORC1-dependent control of the MiT/TFE factors TFEB and TFE3, while it is not involved in mTORC1-dependent phosphorylation of canonical RPS6KB1/S6K1 and EIF4EBP1/4E-BP1 (PubMed:21209915, PubMed:24081491, PubMed:31672913). In low-amino acid conditions, the lysosomal folliculin complex (LFC) is formed on the membrane of lysosomes, which inhibits the GTPase-activating activity of FLCN, inactivates mTORC1 and maximizes nuclear translocation of TFEB and TFE3 (PubMed:31672913). Upon amino acid restimulation, RRAGA/RagA (or RRAGB/RagB) nucleotide exchange promotes disassembly of the LFC complex and liberates the GTPase-activating activity of FLCN, leading to activation of mTORC1 and subsequent cytoplasmic retention of TFEB and TFE3 (PubMed:31672913). Indirectly acts as a positive regulator of Wnt signaling by promoting mTOR-dependent cytoplasmic retention of MiT/TFE factor TFE3 (PubMed:31272105). Required for the exit of hematopoietic stem cell from pluripotency by promoting mTOR-dependent cytoplasmic retention of TFE3, thereby increasing Wnt signaling (PubMed:30733432). Acts as an inhibitor of browning of adipose tissue by regulating mTOR-dependent cytoplasmic retention of TFE3 (By similarity). In response to flow stress, regulates STK11/LKB1 accumulation and mTORC1 activation through primary cilia: may act by recruiting STK11/LKB1 to primary cilia for activation of AMPK resided at basal bodies, causing mTORC1 down-regulation (PubMed:27072130). Together with FNIP1 and/or FNIP2, regulates autophagy: following phosphorylation by ULK1, interacts with GABARAP and promotes autophagy (PubMed:25126726). Required for starvation-induced perinuclear clustering of lysosomes by promoting association of RILP with its effector RAB34 (PubMed:27113757). UniProt
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Subunit Structure
Interacts (via C-terminus) with FNIP1 or FNIP2 (via C-terminus) (PubMed:17028174, PubMed:18403135, PubMed:18663353, PubMed:27353360). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913). Interaction with FNIP1 or FNIP2 mediates indirect interaction with the PRKAA1, PRKAB1 and PRKAG1 subunits of 5'-AMP-activated protein kinase (AMPK) (PubMed:17028174). Interacts with HSP90AA1 in the presence of FNIP1 (PubMed:27353360). Interacts with HSP70, STUB1, CDC37, AHSA1, CCT2, STIP1, PTGES3 and PPP5C (PubMed:27353360). Interacts with GABARAP; interaction takes place in the presence of FNIP1 and/or FNIP2 (PubMed:25126726). Interacts with RILP; the interaction is direct and promotes association between RILP and RAB34 (PubMed:27113757). Interacts with KIF3A and KIF3B (PubMed:27072130). UniProt
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