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}.
Sequence: MNAIVALCHFCELHGPRTLFCTEVLHAPLPQGAGSGDSPGQVEQAEEEEGGIQMSSRVRAHSPAEGASTDSSSPGPKKSDMCEGCRSLAVGHPGYISHDKETSIKYVSHQHPNHPQLFSIVRQACVRSLSCEVCPGREGPIFFGDEQHGFVFSHTFFIKDSLARGFQRWYSIIAIMMDRIYLINSWPFLLGKIRGIISELQGKALKVFEAEQFGCPQRAQRMNTAFTPFLHQRNGNAARSLTSLTSDDNLWACLHTSFAWLLKACGSRLTEKLLEGAPTEDTLVQMEKLADLEEESESWDNSEAEEEEKAPATAEGAEGRELASCPTESSFLSACGSWQPPKLSVFKSLRHMRQVLGAPSFRMLAWHVLMGNQVIWKSRDVNLVHSAFEVLRTMLPVGCVRIIPYSSQYEEAYRCNFLGLSPPVPIPAHVLASEFVVVVEVHTATRSNPHPAGCEDDQSLSKYEFVVTSGSPVAADRVGPTILNKMEAALTNQNLSVDVVDQCLVCLKEEWMNKVKVLFKFTKVDSRPKEDTQKLLSVLGASEEDNVKLLKFWMTGLSKTYKSHLMSTVRSPTAAESRN
InterPro domains: - IPR037521: Folliculin/SMCR8, tripartite DENN domain (domain) [86-558]
- IPR032035: Folliculin, DENN domain (domain) [345-566]
- IPR021713: Folliculin (family) [1-558]
- IPR037520: Folliculin/SMCR8, longin domain (domain) [105-265]
- IPR044886: Folliculin, DENN domain, C-terminal superfamily (homologous_superfamily) [477-566]
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.
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0098772 (molecular function regulator activity), GO:0005488 (binding), GO:0030234 (enzyme regulator activity), GO:0044877 (protein-containing complex binding), GO:0140677 (molecular function activator activity), GO:0005515 (protein binding), GO:0140678 (molecular function inhibitor activity), GO:0019899 (enzyme binding), GO:0060589 (nucleoside-triphosphatase regulator activity), GO:0004857 (enzyme inhibitor activity), GO:0008047 (enzyme activator activity), GO:0030695 (GTPase regulator activity), GO:0005096 (GTPase activator activity)
Biological Process (BP): GO:0008150 (biological process), GO:0065007 (biological regulation), GO:0050789 (regulation of biological process), GO:0032502 (developmental process), GO:0048519 (negative regulation of biological process), GO:0032501 (multicellular organismal process), GO:0048856 (anatomical structure development), GO:0007275 (multicellular organism development), GO:0019222 (regulation of metabolic process), GO:0050794 (regulation of cellular process), GO:0048523 (negative regulation of cellular process), GO:0009892 (negative regulation of metabolic process), GO:0035295 (tube development), GO:0051172 (negative regulation of nitrogen compound metabolic process), GO:0010605 (negative regulation of macromolecule metabolic process), GO:0048731 (system development), GO:0048513 (animal organ development), GO:0009889 (regulation of biosynthetic process), GO:0051171 (regulation of nitrogen compound metabolic process), GO:0060255 (regulation of macromolecule metabolic process), GO:0031323 (regulation of cellular metabolic process), GO:0009890 (negative regulation of biosynthetic process), GO:0080090 (regulation of primary metabolic process), GO:0031324 (negative regulation of cellular metabolic process), GO:0072001 (renal system development), GO:0007399 (nervous system development), GO:0010556 (regulation of macromolecule biosynthetic process), GO:0031326 (regulation of cellular biosynthetic process), GO:0019219 (regulation of nucleobase-containing compound metabolic process), GO:0010558 (negative regulation of macromolecule biosynthetic process), GO:0031327 (negative regulation of cellular biosynthetic process), GO:0051252 (regulation of RNA metabolic process), GO:0051253 (negative regulation of RNA metabolic process), GO:0001822 (kidney development), GO:0045934 (negative regulation of nucleobase-containing compound metabolic process), GO:0010468 (regulation of gene expression), GO:2001141 (regulation of RNA biosynthetic process), GO:1902679 (negative regulation of RNA biosynthetic process), GO:0006355 (regulation of DNA-templated transcription), GO:0006357 (regulation of transcription by RNA polymerase II), GO:1903507 (negative regulation of nucleic acid-templated transcription), GO:1903506 (regulation of nucleic acid-templated transcription), GO:0045892 (negative regulation of DNA-templated transcription), GO:0000122 (negative regulation of transcription by RNA polymerase II)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:0005737 (cytoplasm), GO:0012505 (endomembrane system), GO:0031410 (cytoplasmic vesicle), GO:0043229 (intracellular organelle), GO:0005768 (endosome), GO:0043227 (membrane-bounded organelle), GO:0043231 (intracellular membrane-bounded organelle), GO:0031982 (vesicle), GO:0097708 (intracellular vesicle), GO:0005634 (nucleus)