Birt-Hogg-Dubé Syndrome (BHD) is caused by mutations in the gene folliculin (FLCN). If we can fully understand how FLCN functions in the cell, we can start to develop novel therapies which will restore signalling when FLCN is mutated. Although this seems like a simple task, research has shown that FLCN is involved in a lot of different cellular processes and the pathways involved are actually very complex.
We know that FLCN forms a complex with two other proteins, named folliculin interacting protein 1 (FNIP1) and FNIP2 respectively, and many studies have shown that the FLCN/FNIP complex acts to modulate the activity of mechanistic target of rapamycin complex 1 (mTORC1) and AMP-activated protein kinase (AMPK). Ramirez Reyes et al., provide a comprehensive review of the known functions of FLCN (1). This blog post will focus on the role of FLCN in mTORC1 signalling. Future blog posts will focus on FLCN and AMPK signalling, and other roles of FLCN discussed in by the authors.
What is mTOR signalling and why is it important?
mTOR signalling is a master regulator of cell metabolism, growth, proliferation, and survival. In cancer cells, these pathways are manipulated to create a favourable environment for cancer progression. Cellular metabolism needs to be increased in order to promote cellular growth and proliferation, and survival of these cells is critical for the growing tumour. It is therefore no surprise that mTOR signalling is often affected in not just cancer but many other diseases including metabolic syndromes and neurodevelopmental disorders. In fact, hyperactivation of mTORC1 signalling has been found in over 80% of cancers. Targeting this pathway is very attractive for anticancer therapy, as restoration of aberrant mTOR signalling in cancer cells can slow or inhibit tumour development.
What is the role of mTOR in BHD?
The role of mTOR in BHD is controversial and there have been conflicting reports in the literature of the effect of the loss of FLCN on mTOR signalling. In some cell lines which have reduced FLCN, mTOR activation is reduced (i.e. less cell growth and proliferation). However, in BHD-derived kidney tumours, FLCN has been shown to have the opposite effect and lead to hyperactivation of mTOR.
To further understand how hyperactivation of mTOR contributes to cancer progression it is important to look at the downstream factors that are activated by this pathway. Two of these factors are the transcription factors TFEB and TFE3 (transcription factor binding to IGHM enhancer B or 3). TFEB and TFE3 are known to regulate the expression of genes involved in a wide range of cellular processes including lysosome biogenesis and autophagy which are both important in the recycling of cellular components and cancer progression. Activation of TFEB and TFE3, and therefore transcription of target genes, has been demonstrated in several cancers.
It has been shown that FLCN prevents the translocation of TFEB and TFE3 to the nucleus and consequently prevents transcription of target genes. Loss of FLCN therefore leads to constitutive activation of TFEB and TFE3 and transcription of target genes. Moreover, a paper published in 2020 by Napolitano et al., demonstrates that depletion of TFEB in a mouse kidney model of BHD completely rescues the disease phenotype (2).
FLCN is an essential modulator of these metabolic processes, however the conflicting evidence in the literature means there are still many questions to be answered to fully understand the interplay between FLCN and mTOR signalling. Further research into understanding the role FLCN plays in mTOR signalling will increase our knowledge of tumour progression and facilitate the identification of potential novel therapies. In addition to running the BHD Foundation to provide advocacy and support, the Myrovlytis Trust are committed to uncovering the role of FLCN and developing new therapies through funding research and bringing the research community together to tackle these important questions.
1. Reyes JMJR, Cuesta R, Pause A. Folliculin: A Regulator of Transcription Through AMPK and mTOR Signaling Pathways. Front Cell Dev Biol. 2021;
2. Napolitano G, Di Malta C, Esposito A, de Araujo MEG, Pece S, Bertalot G, et al. A substrate-specific mTORC1 pathway underlies Birt–Hogg–Dubé syndrome. Nature [Internet]. 2020 Sep 24 [cited 2021 May 18];585(7826):597–602. Available from: https://www.nature.com/articles/s41586-020-2444-0