Dual-functional GLA coordinates mTORC1 signaling and autophagy-lysosomal pathway to drive melanoma growth

Genetic inactivation of alpha-galactosidase A (GLA) causes Fabry disease, which is characterized by early cutaneous lesions such as angiokeratomas. However, the role of GLA in malignancies like melanoma remains poorly understood. Here, we show that high expression of GLA correlates with tumor development and progression, including in melanoma. GLA overexpression enhances B16 melanoma cell survival and proliferation by activating mTORC1 signaling, whereas GLA deficiency suppresses mTORC1 and enhances lysosome biogenesis through its downstream transcription factor EB (TFEB). Loss of GLA enzymatic activity also impairs autolysosome formation and autophagic flux, thereby disrupting the autophagy-lysosomal pathway. Mechanistically, the GLA precursor is diverted from the secretory pathway and directly interacts with subunits of the GAP activity toward Rags complex 1 (GATOR1) on the lysosomal surface, sensitizing nutrient-sensing signals upstream of mTORC1. Notably, catalytically inactive GLA mutants retain the ability to activate mTORC1 and promote tumor growth, supporting an enzyme-independent oncogenic function of GLA. Together, these findings reveal a GLA-GATOR1-mTOR regulatory axis critical for melanoma development and identify GLA as a potential biomarker for distinguishing benign angiokeratoma from malignant melanoma.