Signal propagation in cells plays an essential role in the development of the tumour as well as in the course of the immune response and therefore in the development of metabolic disorders, such as diabetes and metabolic syndrome. LAMTOR, which was originally identified including by our group, consists of seven proteins (p14, p18, MP1, HBXIP, p11 –also called LAMTOR1-5 – a RagA and RagC). It coordinates cell division, cell growth, cell death, cell migration and lysosomal positioning (Filipek et al., J Cell Biol 2017) by recruiting the signalling proteins MAPK and mTORC to the lysosome. In a collaboration funded by the Austrian Science Fund (FWF), our research group, together with the group of Klaus Scheffzek and other colleagues at the Biocentre of the Medical University, have succeeded in elucidating the three-dimensional structure of the LAMTOR complex and its impact on signalling (Araujo et al., Science 2017). The LAMTOR1 subunit forms the clamp that binds the other components and tethers the protein complex to the lysosome, the mobile waste disposal and signalling platform of the cell. RagA and RagC, two signal components from the G protein family, are thus aligned with the mTORC signal path and therefore dock into the lysosomal LAMTOR complex (Fig. 1). 

In a collaboration with the group of Andrea Ballabio at TIGEM in Italy, we investigated the role of mTOR in a rare disease (Napolitano et al., Nature 2020). In 1977, three Canadian physicians discovered the eponymous rare autosomal-dominant Birt-Hogg-Dubé (BHD) syndrome. This disorder has been described in over 100 families around the world. The common feature here is the tendency to form kidney and lung cysts as well as skin lesions. The renal cysts often deteriorate and form malignant tumours. mTOR blocks the action of transcription factor TFEB during nutrient uptake. Conversely, TFEB is activated when there is a lack of nutrients and internal reserves have to be used. In this collaboration, we were able to identify for the first time that the renal phenotype (cysts and renal cell carcinoma) in BHD syndrome occurs as a result of constitutive activation of TFEB, which in turn leads to paradoxical mTORC1 hyperactivation in this disease.

Fig. 1 The LAMTOR/Ragulator complex