Lysosomal cholesterol signaling protein (GPR155)

Lysosomal cholesterol signaling protein (GPR155, also known as LYCHOS) is a multidomain lysosomal transmembrane protein with a unique structure containing both a plant-like PIN transporter domain and a class B2-like G protein-coupled receptor (GPCR) domain. It is a cholesterol sensor that operates at the lysosomal membrane, enabling cholesterol-dependent activation of the master metabolic kinase mechanistic target of rapamycin complex 1 (mTORC1), thus coupling lysosomal cholesterol levels to anabolic signaling and cell growth control. The protein directly binds cholesterol via its N-terminal permease-like domain, and its GPCR-like region interacts with the GATOR1 complex to modulate mTORC1 recruitment in response to cholesterol levels. Unlike classical GPCRs, it does not detect extracellular ligands but acts as an intracellular sensor integrating nutrient (cholesterol) status with cell growth pathways. Disruption of GPR155/LYCHOS impairs cholesterol-mediated activation of mTORC1, suggesting it as a potential therapeutic target in cancer and metabolic disorders, though no drugs directly target it yet.

Other names

G protein-coupled receptor 155LYCHOSPGR22DEP.7DEPDC3FLJ31819Integral membrane protein GPR155G-protein coupled receptor PGR22

Drugs targeting this molecule could theoretically modulate cholesterol-activated mTORC1 signaling by inhibiting or activating GPR155/LYCHOS’s cholesterol-sensing activity. There are no reported clinically-approved drugs directly targeting GPR155/LYCHOS as of September 2025.