Folliculin

Definition:

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.

References:

[1]. John C Kennedy, et al. Loss of FLCN inhibits canonical WNT signaling via TFE3. Hum Mol Genet. 2019 Oct 1;28(19):3270-3281. [Content Brief]

[2]. Kuang Shen, et al. Cryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Complex. Cell. 2019 Nov 27;179(6):1319-1329.e8. [Content Brief]

[3]. J Mathieu, et al. Folliculin regulates mTORC1/2 and WNT pathways in early human pluripotency. Nat Commun. 2019 Feb 7;10(1):632. [Content Brief]

[4]. Mingming Zhong, et al. Tumor Suppressor Folliculin Regulates mTORC1 through Primary Cilia. J Biol Chem. 2016 May 27;291(22):11689-97. [Content Brief]

[5]. Y Takagi, et al. Interaction of folliculin (Birt-Hogg-Dubé gene product) with a novel Fnip1-like (FnipL/Fnip2) protein. Oncogene. 2008 Sep 11;27(40):5339-47. [Content Brief]

[6]. Elaine A Dunlop, et al. FLCN, a novel autophagy component, interacts with GABARAP and is regulated by ULK1 phosphorylation. Autophagy. 2014 Oct 1;10(10):1749-60. [Content Brief]

[7]. Rosalie E Lawrence, et al. Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex. Science. 2019 Nov 22;366(6468):971-977. [Content Brief]

[8]. Zhi-Yang Tsun, et al. The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol Cell. 2013 Nov 21;52(4):495-505. [Content Brief]

[9]. Constance S Petit, et al. Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases. J Cell Biol. 2013 Sep 30;202(7):1107-22. [Content Brief]

[10]. Mark R Woodford, et al. The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect. Nat Struct Mol Biol. 2021 Aug;28(8):662-670. [Content Brief]

[11]. Seung-Beom Hong, et al. Inactivation of the FLCN tumor suppressor gene induces TFE3 transcriptional activity by increasing its nuclear localization. PLoS One. 2010 Dec 29;5(12):e15793. [Content Brief]

[12]. Georgina P Starling, et al. Folliculin directs the formation of a Rab34-RILP complex to control the nutrient-dependent dynamic distribution of lysosomes. EMBO Rep. 2016 Jun;17(6):823-41. [Content Brief]

[13]. Masaya Baba, et al. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15552-7. [Content Brief]

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