Zhou, Y., Yang, X., Xu, W., Shen, S., Fan, W., Meng, G., Cheng, Y., Lu, Y., Wei, Y. (2025). Rag GTPases control lysosomal acidification by regulating v-ATPase assembly in Drosophila.  J. Biol. Chem. 301(7): 110400.

FBrf0263041

Research paper

The Rag GTPases play an important role in sensing amino acids and activating the target of rapamycin complex 1, a master regulator of cell metabolism. Previously, we have shown that GDP-bound RagA stimulates lysosome acidification and autophagic degradation, which are essential for young egg chamber survival under starvation in Drosophila. However, the underlying mechanism is unclear. Here, we demonstrate that the GDP-bound RagA breaks the physical interaction between cytosolic chaperonin-containing tailless complex polypeptide 1 (CCT) and vacuolar H+-ATPase (v-ATPase) subunit V1, and thus promotes the assembly of active v-ATPase and increases the lysosomal acidification. Consistently, knockdown of CCT complex components rescued the accumulation of defective autolysosomes in RagA RNAi. Moreover, the knockdown of Lamtor4, a component of lysosomal adaptor and MAPK and mTOR activator (LAMTOR) that anchors Rag GTPases to the lysosome, resulted in autolysosome accumulation, suggesting that Rag GTPases regulate lysosomal acidification depend on their lysosomal localization. Knockdown of the CCT complex components attenuated the autophagic defects in Lamtor 4 RNAi. Our work highlights the interaction between CCT and v-ATPase in regulating lysosomal acidification.

PMC12332402 (PMC) (EuropePMC)