Mammalian RAVE couples V-ATPase assembly to organelle acidification and function

Acidification of lysosomes, endosomes, and the Golgi underpins organelle-specific functions within the endomembrane system. This process is driven by vacuolar-type H-ATPases (V-ATPases), which reversibly assemble from peripheral V and membrane-integral V domains to regulate organelle pH. In yeast, V-V assembly at the vacuole is mediated by the RAVE complex, but V-ATPase assembly in mammalian cells remains less well understood. Here, we systematically define physiological roles of mammalian RAVE. Under basal conditions, mRAVE broadly promotes V-ATPase assembly and organelle acidification. Upon mTORC1 inactivation, mRAVE is recruited to lysosomes and required for the resulting increase in V-ATPase assembly and catabolic activity. Loss of mRAVE disrupts organelle acidification, leading to suppression of lysosomal catabolism, accumulation of dysfunctional lysosomes and compensatory lysosomal exocytosis. Restoring lysosomal pH rescues basal function in mRAVE-deficient cells but not the mTORC1-regulated increase in catabolic activity. Thus, mRAVE is an essential V-ATPase assembly factor that couples acidification to organelle function and nutrient signaling.