Lysosomes are enzyme-containing organelles that break down macromolecules in order to recycle their components and maintain cellular homeostasis. Lysosome dysfunction can cause an array of diseases, including Gaucher’s Disease, Niemann Pick Disease and even some cancers (Appelqvist et al., 2013). A number of recent studies suggest that the lysosome may be central to the development of some forms of hereditary kidney cancer.
In October 2013, it was reported by two independent groups that FLCN is recruited to the lysosome by the Rag proteins upon amino acid depletion, and rapidly activates mTORC1 signalling upon amino acid reintroduction (Petit et al., 2013, Tsun et al., 2013). In January 2014, it was shown that TFE3 is recruited to the lysosome by the Rag proteins and inactivated by mTORC1 under amino acid sufficiency and that FLCN was required for this. During amino acid depletion, TFE3 is released from the lysosome and translocates to the nucleus, where it activates the expression of target genes, including lysosome and autophagy genes (Martina et al., 2014).
In February 2014, two papers were published back to back in Cell, showing that TSC2 exerts its control on Rheb and mTORC1 at the lysosome. Menon et al. (2014) report that, in the absence of insulin, Rheb recruits TSC2 to the lysosome surface, where it inhibits Rheb and thus also mTORC1 signalling. Conversely, insulin signalling leads to TSC2 phosphorylation via PI3K signalling, causing TSC2 to dissociate from the lysosome, allowing mTORC1 activation by Rheb and the Rag proteins to proceed. Demetriades et al. (2014) show that under amino acid starvation, TSC2 is recruited to the lysosome by the Rag proteins, where it inhibits Rheb, causing mTORC1 to dissociate from the lysosome surface and become inactive. Taken together, the two studies show that both insulin signalling and amino acids are required for TSC2 to dissociate from lysosomes, and allow mTORC1 to be fully activated.
Overall, it seems that under nutrient sufficiency TSC2 and FLCN are located in the cytoplasm, mTORC1 signalling is active, and TFE3 is held at the lysosome, thus inhibiting autophagy. Under nutrient depletion, TSC2 and FLCN are both recruited to the lysosome where TSC2 inhibits mTORC1, TFE3 is released from the lysosome and activates autophagy. Upon the reintroduction of nutrients, TSC2 dissociates from the lysosome, mTORC1 is recruited to the lysosome by the Rag proteins and activated by FLCN, and TFE3 once more becomes inactive. Thus, is seems that these three kidney cancer genes ensure that cells accurately and rapidly switch between anabolic and catabolic cellular metabolism in response to nutrient supply.
Although mutations in all three genes cause kidney cancer, they function at different points in the mTOR signalling pathway, meaning that the loss of each gene causes different metabolic defects. Uncoupling of cellular metabolism from nutrient supply is a common feature of many cancers, including kidney cancer where dysregulated autophagy seems to be a common feature. In wild type cells, a reduction of amino acids inhibits mTORC1 signalling and activates autophagy, and readdition of amino acids activates mTORC1 signalling and inhibits autophagy. Indeed, TSC2-null cells under amino acid depletion show increased mTORC1 signalling, and reduced autophagy (Demetriades et al., 2014, Menon et al., 2014); FLCN-null cells show reduced mTORC1 signalling and increased autophagy following amino acid reintroduction (Martina et al., 2014, Petit et al., 2013, Tsun et al., 2013); and TFE3-null cells show reduced autophagy in response to amino acid depletion (Martina et al., 2014). These differences may explain why kidney cancers caused by these genes have such different histologies and malignant behaviour: TFE3-associated tumours are generally papillary and clinically aggressive (Kuroda et al., 2012); FLCN-associated tumours are most commonly chromophobe, slow growing and rarely metastasise (Stamatakis et al., 2013); and TSC-associated tumours are usually benign angiomyolipomas.
Cellular localisation is likely to be an important factor in allowing proteins with multiple functions, such as mTOR and FLCN, to integrate multiple signals and regulate multiple outcomes. Indeed, it seems that at least three kidney cancer genes cluster at the lysosome to regulate cellular homeostasis in response to nutrient supply. How this insight can be exploited to develop therapies for kidney cancer remains to be seen, but it is possible that drugs targeting lysosome structure or function, such as Miglustat or lysosome enzyme replacement therapies, may be a worthwhile avenue of investigation.
- Appelqvist H, Wäster P, Kågedal K, & Öllinger K (2013). The lysosome: from waste bag to potential therapeutic target. Journal of molecular cell biology, 5 (4), 214-26 PMID: 23918283
- Demetriades C, Doumpas N, & Teleman AA (2014). Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2. Cell, 156 (4), 786-99 PMID: 24529380
- Kuroda N, Mikami S, Pan CC, Cohen RJ, Hes O, Michal M, Nagashima Y, Tanaka Y, Inoue K, Shuin T, & Lee GH (2012). Review of renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions with focus on pathobiological aspect. Histology and histopathology, 27 (2), 133-40 PMID: 22207547
- Martina JA, Diab HI, Lishu L, Jeong-A L, Patange S, Raben N, & Puertollano R (2014). The nutrient-responsive transcription factor TFE3 promotes autophagy, lysosomal biogenesis, and clearance of cellular debris. Science signaling, 7 (309) PMID: 24448649
- Menon S, Dibble CC, Talbott G, Hoxhaj G, Valvezan AJ, Takahashi H, Cantley LC, & Manning BD (2014). Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell, 156 (4), 771-85 PMID: 24529379
- Petit CS, Roczniak-Ferguson A, & Ferguson SM (2013). Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases. The Journal of cell biology, 202 (7), 1107-22 PMID: 24081491
- Stamatakis L, Metwalli AR, Middelton LA, & Marston Linehan W (2013). Diagnosis and management of BHD-associated kidney cancer. Familial cancer, 12 (3), 397-402 PMID: 23703644
- Tsun ZY, Bar-Peled L, Chantranupong L, Zoncu R, Wang T, Kim C, Spooner E, & Sabatini DM (2013). The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Molecular cell, 52 (4), 495-505 PMID: 24095279
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.