RRAGC, also known as Ras related GTP binding C, is a key component of the Rag-GTPase heterodimer central to the mTORC1 pathway. This pathway regulates cell growth in response to nutritional status, with amino acids modulating mTORC1 activation via Rag GTPases [1,4]. RRAGC is involved in lysosomal biogenesis, autophagy, and lipid metabolism, and its dysregulation is associated with diseases like Birt-Hogg-Dubé syndrome, follicular lymphoma, and a fatal mTORopathy of early childhood [2,3,5].

In a mouse model of Birt-Hogg-Dubé syndrome, constitutive activation of TFEB, a downstream target of mTORC1 whose phosphorylation depends on RRAGC, was the main driver of kidney abnormalities and mTORC1 hyperactivity. Depletion of TFEB in these mice rescued the disease phenotype and normalized mTORC1 activity, highlighting the role of RRAGC-mediated TFEB phosphorylation in this disorder [2]. In HEK293 cell models and patient-derived skin fibroblasts with de novo missense variants in RRAGC, there was increased cell size, dysregulation of mTOR-related signaling, and decoupling of mTOR subcellular localization from the metabolic state, consistent with constitutive overactivation of the mTORC1 pathway [3].

In conclusion, RRAGC is essential for the proper regulation of the mTORC1 pathway, influencing processes like lysosomal biogenesis, autophagy, and lipid metabolism. Studies using mouse models and cell lines have revealed its role in diseases such as Birt-Hogg-Dubé syndrome and a fatal early-onset mTORopathy. Understanding RRAGC's function provides insights into the mechanisms of these diseases and may offer potential therapeutic targets.