RRAGC, also known as Ras related GTP binding C, is a key component of the Rag-GTPase heterodimer central to the mTORC1 function. The mTORC1 pathway is crucial for regulating cell growth in response to nutritional status, and RRAGC is involved in amino-acid-mediated signaling to mTORC1 [1,3,4].

In a mouse model of Birt-Hogg-Dubé syndrome, constitutive activation of TFEB, a downstream target of mTORC1, was found to be the main driver of kidney abnormalities and mTORC1 hyperactivity. The phosphorylation of TFEB by mTORC1 is strictly dependent on the amino-acid-mediated activation of RRAGC, highlighting the role of RRAGC in this substrate-specific mTORC1 pathway [2]. In addition, de novo missense variants in RRAGC in infants led to dilated cardiomyopathy, hepatopathy, and brain abnormalities, with studies in patient-derived fibroblasts showing dysregulation of mTOR-related signaling, consistent with constitutive overactivation of the mTORC1 pathway [3].

In conclusion, RRAGC is essential for the proper functioning of the mTORC1 pathway, which is vital for cell growth regulation in response to nutritional cues. Studies using mouse models and patient-derived cells with RRAGC variants have revealed its role in diseases such as Birt-Hogg-Dubé syndrome and a fatal early-onset mTORopathy, contributing to our understanding of the underlying disease mechanisms.

References:

1. Sancak, Yasemin, Peterson, Timothy R, Shaul, Yoav D, Bar-Peled, Liron, Sabatini, David M. 2008. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. In Science (New York, N.Y.), 320, 1496-501. doi:10.1126/science.1157535. https://pubmed.ncbi.nlm.nih.gov/18497260/

2. Napolitano, Gennaro, Di Malta, Chiara, Esposito, Alessandra, Huber, Lukas A, Ballabio, Andrea. 2020. A substrate-specific mTORC1 pathway underlies Birt-Hogg-Dubé syndrome. In Nature, 585, 597-602. doi:10.1038/s41586-020-2444-0. https://pubmed.ncbi.nlm.nih.gov/32612235/

3. Reijnders, Margot R F, Seibt, Annette, Brugger, Melanie, Poulter, James A, Distelmaier, Felix. 2023. De novo missense variants in RRAGC lead to a fatal mTORopathy of early childhood. In Genetics in medicine : official journal of the American College of Medical Genetics, 25, 100838. doi:10.1016/j.gim.2023.100838. https://pubmed.ncbi.nlm.nih.gov/37057673/

4. Valenstein, Max L, Lalgudi, Pranav V, Gu, Xin, Chivukula, Raghu R, Sabatini, David M. 2024. Rag-Ragulator is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2322755121. doi:10.1073/pnas.2322755121. https://pubmed.ncbi.nlm.nih.gov/39163330/