mRAVE governs lysosomal catabolism through basal and mTORC1-regulated V-ATPase assembly.

Abstract

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), proton pumps that reversibly assemble from peripheral V1 and membrane-integral Vo domains to regulate organelle pH. In yeast, V1-Vo assembly at the vacuole is mediated by the RAVE complex, but V-ATPase assembly in mammalian cells remains less well understood. Here, we systematically characterize physiological roles of the mammalian RAVE complex, composed of the subunits Dmxl1 or Dmxl2, Wdr7 and Rogdi. Under basal conditions, mRAVE broadly promotes V-ATPase assembly and luminal acidification of endomembrane organelles. 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 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.