Ras-related GTP-binding protein D (RagD)

Ras-related GTP-binding protein D (RagD), encoded by the RRAGD gene, is a member of the Ras-related small GTPase superfamily and a critical component of the nutrient-sensing machinery that regulates the mechanistic target of rapamycin complex 1 (mTORC1) pathway (UniProt Q9NQL2; Science 2017, 356:1188-1193). RagD functions as an obligate heterodimer with either RagA or RagB, and its nucleotide-bound state—active when GDP-bound—is essential for recruiting mTORC1 to the lysosomal surface in response to amino acid availability (PubMed: 24095279; UniProt Q9NQL2). Once localized to the lysosome, mTORC1 is activated by Rheb, promoting cell growth and metabolism while inhibiting catabolic processes like autophagy (Science 2017, 356:1188-1193; PubMed: 20381137). Mutations in RRAGD are associated with "ragopathies," such as autosomal dominant kidney hypomagnesemia and dilated cardiomyopathy, which are characterized by constitutive activation of non-canonical mTORC1 signaling and subsequent suppression of the transcription factor TFEB (PubMed: 32612235; PubMed: 30249034). These mutations often lead to TFEB being trapped in the cytoplasm, preventing the expression of genes required for lysosomal biogenesis and autophagy (PubMed: 38113741). In cancer, RagD is frequently upregulated by MiT/TFE transcription factors, supporting the high metabolic demands of tumor cells (Science 2017, 356:1188-1193). Therapeutic strategies targeting RagD include small-molecule inhibitors like BC-LI-0186, which disrupts the interaction between RagD and leucyl-tRNA synthetase (Tocris Bioscience). Additionally, downstream mTOR inhibitors like rapamycin and SGLT2 inhibitors like dapagliflozin are being explored for the management of RagD-associated diseases (PubMed: 38113741). Despite its potential, targeting RagD presents challenges due to its essential role in normal cell physiology and the risk of on-target toxicities (PubMed: 34257288).

Other names

RRAGDRag DRas-related GTP binding DBA11D8.2.1DKFZP761H171

RagD forms a heterodimer with RagA or RagB to recruit mTORC1 to the lysosome in an amino acid-dependent manner (UniProt Q9NQL2). Drugs like BC-LI-0186 inhibit the interaction between RagD and leucyl-tRNA synthetase (LRS), preventing the activation of the RagD-containing complex and subsequent mTORC1 recruitment (Tocris Bioscience; PubMed: 22575674).