Ras-related GTP-binding protein C (RagC) (RagC)

Ras-related GTP-binding protein C (RagC) is a small GTPase that plays a pivotal role in the nutrient-sensing pathway that activates the mechanistic target of rapamycin complex 1 (mTORC1). It functions as part of a heterodimer with RagA or RagB to recruit mTORC1 to the lysosomal surface, where it can be activated by Rheb. Recent research has identified that specific lysine residues on RagC (K15, K23, and K211) undergo β-hydroxybutyrylation (Kbhb), a post-translational modification induced by elevated levels of the ketone body β-hydroxybutyrate (BHB) during fasting or ketogenic states (He et al., 2024, Molecular Cell). This modification is catalyzed by the acetyltransferase p300 and serves to enhance the interaction between RagC and the mTORC1 component Raptor, thereby driving mTORC1 signaling independently of amino acid levels. In pathological contexts, such as hepatocellular carcinoma, this mechanism allows tumor cells to maintain growth signals even in nutrient-poor environments, identifying RagC β-hydroxybutyrylation as a potential therapeutic target. While direct inhibitors of RagC Kbhb are not yet clinically available, the pathway can be modulated via p300 inhibitors or HDAC inhibitors, which act as the "writer" and "eraser" of this modification, respectively. Targeting this specific metabolic-epigenetic axis offers a novel approach to treating cancers and metabolic diseases characterized by dysregulated mTORC1 activity.

Other names

RRAGCGTPase RagCTIBESRas-related GTP-binding protein Cβ-hydroxybutyrylated RagC

Inhibition of p300-mediated β-hydroxybutyrylation of RagC to prevent mTORC1 lysosomal recruitment and subsequent activation.