Protein: Folliculin (BHD skin lesion fibrofolliculoma protein) (Birt-Hogg-Dube syndrome protein) (Q8NFG4)
Organism: Homo sapiens (Human)
Function: Multi-functional protein, involved in both the cellular response to amino acid availability and in the regulation of glycolysis. 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. Regulates glycolysis by binding to lactate dehydrogenase LDHA, acting as an uncompetitive inhibitor. 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. The GTPase-activating activity is inhibited during starvation and activated in presence of nutrients. 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. 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. 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. Indirectly acts as a positive regulator of Wnt signaling by promoting mTOR-dependent cytoplasmic retention of MiT/TFE factor TFE3. Required for the exit of hematopoietic stem cell from pluripotency by promoting mTOR-dependent cytoplasmic retention of TFE3, thereby increasing Wnt signaling. Acts as an inhibitor of browning of adipose tissue by regulating mTOR-dependent cytoplasmic retention of TFE3 (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). 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. Together with FNIP1 and/or FNIP2, regulates autophagy: following phosphorylation by ULK1, interacts with GABARAP and promotes autophagy. Required for starvation-induced perinuclear clustering of lysosomes by promoting association of RILP with its effector RAB34.
Subcellular location: Lysosome membrane {ECO:0000269|PubMed:24081491, ECO:0000269|PubMed:24095279, ECO:0000269|PubMed:27113757, ECO:0000269|PubMed:29848618, ECO:0000269|PubMed:31672913}. Cytoplasm, cytosol {ECO:0000269|PubMed:17028174, ECO:0000269|PubMed:18663353, ECO:0000269|PubMed:24081491, ECO:0000269|PubMed:24095279, ECO:0000269|PubMed:29848618, ECO:0000269|PubMed:31672913}. Cell projection, cilium {ECO:0000269|PubMed:23784378, ECO:0000269|PubMed:27072130}. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000269|PubMed:23784378}. Cytoplasm, cytoskeleton, spindle {ECO:0000269|PubMed:23784378}. Nucleus {ECO:0000269|PubMed:17028174, ECO:0000269|PubMed:18663353}. Note=Localizes to lysosome membrane in amino acid-depleted conditions and relocalizes to the cytosol upon refeeding (PubMed:24095279, PubMed:29848618, PubMed:31672913). Colocalizes with FNIP1 and FNIP2 in the cytoplasm (PubMed:17028174, PubMed:18663353). Also localizes to motile and non-motile cilia, centrosomes and the mitotic spindle (PubMed:23784378). {ECO:0000269|PubMed:17028174, ECO:0000269|PubMed:18663353, ECO:0000269|PubMed:23784378, ECO:0000269|PubMed:24095279, ECO:0000269|PubMed:29848618, ECO:0000269|PubMed:31672913}.
Interaction partners:
- Folliculin-interacting protein 2
- Ras-related GTP-binding protein C
- Folliculin-interacting protein 1
- Ras-related GTP-binding protein A
- Ras-related GTP-binding protein B
- Ras-related GTP-binding protein D
- Neutral amino acid transporter 9
- Ragulator complex protein LAMTOR1
- Ragulator complex protein LAMTOR4
- Ragulator complex protein LAMTOR2
Sequence:
MNAIVALCHFCELHGPRTLFCTEVLHAPLPQGDGNEDSPGQGEQAEEEEGGIQMNSRMRAHSPAEGASVESSSPGPKKSDMCEGCRSLAAGHPGYISHDKETSIKYVSHQHPSHPQLFSIVRQACVRSLSCEVCPGREGPIFFGDEQHGFVFSHTFFIKDSLARGFQRWYSIITIMMDRIYLINSWPFLLGKVRGIIDELQGKALKVFEAEQFGCPQRAQRMNTAFTPFLHQRNGNAARSLTSLTSDDNLWACLHTSFAWLLKACGSRLTEKLLEGAPTEDTLVQMEKLADLEEESESWDNSEAEEEEKAPVLPESTEGRELTQGPAESSSLSGCGSWQPRKLPVFKSLRHMRQVLGAPSFRMLAWHVLMGNQVIWKSRDVDLVQSAFEVLRTMLPVGCVRIIPYSSQYEEAYRCNFLGLSPHVQIPPHVLSSEFAVIVEVHAAARSTLHPVGCEDDQSLSKYEFVVTSGSPVAADRVGPTILNKIEAALTNQNLSVDVVDQCLVCLKEEWMNKVKVLFKFTKVDSRPKEDTQKLLSILGASEEDNVKLLKFWMTGLSKTYKSHLMSTVRSPTASESRN