FLCN Gene

The FLCN gene (FLCN stands for folliculin) is a protein-coding gene located on chromosome 17p11.2. Alternative splicing of this gene results in two transcript variants encoding different isoforms. Associated signaling pathways include cellular responses to stimuli and viral mRNA translation.

The FLCN gene is located in the Smith-Magenis syndrome region on chromosome 17. Mutations in this gene are associated with Birt-Hogg-Dubé syndrome, which is characterized by fibrofolliculomas, renal tumors, pulmonary cysts and pneumothorax.

The encoded protein, folliculin, is a multifunctional protein involved in both the cellular response to amino acid availability and the regulation of glycolysis (Baba M et al. 2006). Folliculin is a GTPase-activating protein that plays a key role in the cellular response to amino acid availability by regulating the mTORC1 signaling cascade, which controls the MiT/TFE factors TFEB and TFE3 (Lawrence RE et al. 2019). Folliculin regulates glycolysis by binding to the lactate dehydrogenase LDHA and acts as a non-competitive inhibitor (Woodford MR et al. 2021). Activates mTORC1 by acting as a GTPase-activating protein: specifically stimulates GTP hydrolysis by RRAGC/RagC or RRAGD/RagD, promotes conversion to the GDP-bound state of RRAGC/RagC or RRAGD/RagD and thereby activates the kinase activity of mTORC1. Under amino acid-depleted conditions, the lysosomal folliculin complex (LFC) is formed at the membrane of the lysosomes, which inhibits the GTPase-activating activity of FLCN, inactivates mTORC1 and maximizes the nuclear translocation of TFEB and TFE3 (Mathieu J et al. 2019).

1. Baba M et al. (2006) 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 103:15552-15527.
2. Lawrence RE et al. (2019) Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex. Science 366:971-977.
3. Mathieu J et al. (2019) Folliculin regulates mTORC1/2 and WNT pathways in early human pluripotency. Nat Commun 10:632.

4. PDQ Cancer Genetics Editorial Board (2023) Birt-Hogg-Dubé Syndrome (PDQ®): Health Professional Version. 2023 Oct 30. in: PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US) 2002-. PMID: 33724752.

5. Woodford MR et al. (2021) The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect. Nat Struct Mol Biol 28:662-670.