Folliculin

Folliculin is a protein that is expressed in a number of normal tissues such as skin, lung and kidney. Its exact function is still unknown. Folliculin is the product of the FLCN gene. This 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.

Recent evidence suggests that FLCN acts as a tumor suppressor via an interaction with the mTOR energy processing pathway, and its absence contributes to the development of BHDS-associated renal tumors.

Folliculin mutations are associated with Birt-Hogg-Dubé syndrome, which is characterized by fibrofolliculomas, renal tumors, lung cysts, and pneumothorax. A number of mutations are known, including deletions, substitutions, and duplications, which are thought to lead to protein shortening and consequent loss of function

There may be subtypes of Birt-Hogg-Dubé syndrome, as lung cysts are the predominant feature in some families and skin and kidney manifestations are less common. In addition, mutations may be specific to certain ethnicities, as Japanese and Caucasian patients have been found to have different mutation distributions and unique alterations.

The identification of a somatic second hit in most renal tumors associated with Birt-Hogg-Dubé syndrome (BHD) strongly suggests that FLCN acts as a tumor suppressor. Both somatic point mutations (variants) in the wild-type FLCN allele and loss of heterozygosity at chromosome 17p have been identified, with the former appearing to be the more common mechanism for inactivation of the second FLCN allele (PDQ Cancer Genetics Editorial Board 2023).

The exact mechanisms by which FLCN inactivation leads to tumorigenesis are still unclear. However, folliculin has been implicated as a component of the cellular energy sensing system. Folliculin interacts with AMPK in conjunction with one of two novel folliculin-interacting proteins, FNIP1 and FNIP2. AMPK is an important cellular energy and nutrient sensor that regulates the activity of mTOR in response to these stimuli. In addition, both folliculin and FNIP1 are phosphorylated by AMPK, although the significance of this post-translational modification is not clear. The C-terminal domain of FLCN is required for interaction with FNIP1 and FNIP2. Most, but not all, tumor-associated variants of FLCN suggest a truncated protein lacking this C-terminal domain or appear to destabilize the FLCN protein (Nahorski MS et al. 2011).

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. Nahorski MS et al (2011) Birt Hogg-Dubé syndrome-associated FLCN mutations disrupt protein stability. Hum Mutat 32: 921-929.

5. 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.

6. 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.