Exploring a molecular link between Birt-Hogg-Dubé Syndrome and Tuberous Sclerosis.

Tuberous Sclerosis (TSC) is an autosomal disorder caused by mutations in the genes TSC1 or TSC2. It is characterised by the development of tumours that affect several organs including the brain, heart, kidney, lung and skin. Most TSC-associated tumours are benign however malignant tumours do occur, particularly in the kidneys. As such, TSC and Birt-Hogg-Dubé Syndrome (BHD) share some similar features as well as manifestations that are unique to each condition. Like folliculin (FLCN), which is mutated in BHD, TSC1 and TSC2 also regulate the activity of mTOR signalling. We recently published a blog that reviewed the function of FLCN in regulating mTOR signalling. The authors of the review highlighted work which demonstrated that in kidney tumours derived from BHD patients, the loss of FLCN led to hyperactivation of mTOR. Similarly, in TSC, loss of either TSC1 or TSC2 leads to hyperactivation of mTOR which is believed to be the main driver of tumourigenesis.

A recent paper by Alesi et al., investigated the role that TSC1 and TSC2 play in the regulation of lysosome biogenesis and mTOR signalling (1). Lysosomes are organelles responsible for degradation and recycling of cellular waste. Studying lysosomes is important in this context as they have been increasingly shown to be a driver of tumourigenesis. The activity of mTORC1 (a key player in the mTOR signalling pathway) tightly regulates the transcription factors TFEB and TFE3, master regulators of lysosome gene expression, biogenesis and autophagy. In theory, hyperactivation of mTOR signalling should result in prevention of TFEB translocating to the nucleus where it is active. However, there is conflicting evidence of this in the literature in the context of TSC. This present study shows that despite high mTORC1 activity, the localisation of TFEB is predominantly nuclear. Of interest, this has also been shown for a mouse model of BHD-associated kidney cancer in a paper by Napolitano et al., indicating that TFEB may be a driver of tumourigenesis in both TSC and BHD. This is the opposite of what you would expect and so it is important to understand why this happens.

The authors made use of multiple different models to examine TFEB activity in cells lacking TSC2. In a mouse model of TSC which develops kidney cysts they found a 3-fold increase in the number of lysosomes in the tumours compared to adjacent healthy tissue, indicating an increase in TFEB activity in tumours. They also demonstrated an increase of TFEB with a predominantly nuclear localisation in cells lacking TSC2 in vitro. They confirmed that the nuclear TFEB was active in these cells and that this activity led to an increase in cell proliferation, which is required for tumourigenesis.

As FLCN has been shown to be important for TFEB regulation, Alesi et al., next looked at a combined effect of FLCN and TSC2. They depleted TSC2 and FLCN either alone or in combination in vitro and as expected, saw a significant increase in TFEB nuclear localisation and activity when either TSC2 or FLCN were depleted alone. This effect was further enhanced when both TSC2 and FLCN were depleted. The ability of FLCN to regulate TFEB activity is mediated by the proteins RAGC and RAGD which activate mTORC1. The authors demonstrated an increase in the expression of RAGC and RAGD in TSC2 deficient cells, as well as in FLCN-deficient cells and cells lacking both TSC2 and FLCN. They suggested that this could represent an additional mechanism for sustained mTORC1 activity in TSC2 and/or FLCN-depleted cells. The authors stated that the combined loss of TSC2 and FLCN resulting in an even stronger nuclear localisation and thus activity of TFEB implies that there is a pathogenic link between TSC and BHD and that TFEB may represent a therapeutic target for both these rare conditions.

At the BHD Foundation and Myrovlytis Trust we found this paper exciting. The rarity and complexity of conditions such as BHD and TSC present many research challenges. Identification of common pathways that may be targeted therapeutically against multiple conditions is an extremely attractive approach. Further research needs to be performed to investigate if TFEB can be a therapeutic target for alleviating kidney disease in both TSC and BHD.


1.        Alesi N, Akl EW, Khabibullin D, Liu HJ, Nidhiry AS, Garner ER, et al. TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism. Nat Commun. 2021;12(1).

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