Protein: Folliculin (Birt-Hogg-Dube syndrome protein homolog) (Q76JQ2)
Organism: Rattus norvegicus (Rat)
Function: Multi-functional protein, involved in both the cellular response to amino acid availability and in the regulation of glycolysis (By similarity). 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 (By similarity). Regulates glycolysis by binding to lactate dehydrogenase LDHA, acting as an uncompetitive inhibitor (By similarity). 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 (By similarity). The GTPase-activating activity is inhibited during starvation and activated in presence of nutrients (By similarity). 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 (By similarity). 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 (By similarity). 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 (By similarity). Indirectly acts as a positive regulator of Wnt signaling by promoting mTOR-dependent cytoplasmic retention of MiT/TFE factor TFE3 (By similarity). Required for the exit of hematopoietic stem cell from pluripotency by promoting mTOR-dependent cytoplasmic retention of TFE3, thereby increasing Wnt signaling (By similarity). Involved in the control of embryonic stem cells differentiation; together with LAMTOR1 it is necessary to recruit and activate RRAGC/RagC and RRAGD/RagD at the lysosomes, and to induce exit of embryonic stem cells from pluripotency via non-canonical, mTOR-independent TFE3 inactivation (By similarity). 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 (By similarity). Together with FNIP1 and/or FNIP2, regulates autophagy: following phosphorylation by ULK1, interacts with GABARAP and promotes autophagy (By similarity). Required for starvation-induced perinuclear clustering of lysosomes by promoting association of RILP with its effector RAB34 (By similarity).
Subcellular location: Lysosome membrane {ECO:0000250|UniProtKB:Q8NFG4}. Cytoplasm, cytosol {ECO:0000250|UniProtKB:Q8NFG4}. Cell projection, cilium {ECO:0000250|UniProtKB:Q8NFG4}. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000250|UniProtKB:Q8NFG4}. Cytoplasm, cytoskeleton, spindle {ECO:0000250|UniProtKB:Q8NFG4}. Nucleus {ECO:0000250|UniProtKB:Q8NFG4}. Note=Localizes to lysosome membrane in amino acid-depleted conditions and relocalizes to the cytosol upon refeeding. Colocalizes with FNIP1 and FNIP2 in the cytoplasm. Also localizes to motile and non-motile cilia, centrosomes and the mitotic spindle. {ECO:0000250|UniProtKB:Q8NFG4}.
Interaction partners:
- Folliculin interacting protein 1
- Folliculin interacting protein 2
- Ras-related GTP-binding protein
- Ras-related GTP-binding protein B
- Ras-related GTP-binding protein A
- Ras-related GTP-binding protein
- Neutral amino acid transporter 9
- Ragulator complex protein LAMTOR1
- Ragulator complex protein LAMTOR3
- Late endosomal/lysosomal adaptor, MAPK and MTOR activator 2.
Sequence:
MNAIVALCHFCELHGPRTLFCTEVLHAPLPQGAGSGDSPGQVEQAEEEEGGIQMSSRVRAHSPAEGASTDSSSPGPKKSDMCEGCRSLAVGHPGYISHDKETSIKYVSHQHPNHPQLFSIVRQACVRSLSCEVCPGREGPIFFGDEQHGFVFSHTFFIKDSLARGFQRWYSIIAIMMDRIYLINSWPFLLGKIRGIISELQGKALKVFEAEQFGCPQRAQRMNTAFTPFLHQRNGNAARSLTSLTSDDNLWACLHTSFAWLLKACGSRLTEKLLEGAPTEDTLVQMEKLADLEEESESWDNSEAEEEEKAPATAEGAEGRELASCPTESSFLSACGSWQPPKLSVFKSLRHMRQVLGAPSFRMLAWHVLMGNQVIWKSRDVNLVHSAFEVLRTMLPVGCVRIIPYSSQYEEAYRCNFLGLSPPVPIPAHVLASEFVVVVEVHTATRSNPHPAGCEDDQSLSKYEFVVTSGSPVAADRVGPTILNKMEAALTNQNLSVDVVDQCLVCLKEEWMNKVKVLFKFTKVDSRPKEDTQKLLSVLGASEEDNVKLLKFWMTGLSKTYKSHLMSTVRSPTAAESRN