The R2TP Complex Couples mTORC1 Signaling to Vacuolar ATPase Assembly and Lysosomal Function.
The R2TP Complex Couples mTORC1 Signaling to Vacuolar ATPase Assembly and Lysosomal Function.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Macau, MO · Author affiliation
State Key Laboratory of Mechanism and Quality of Chinese Medicine, University of Macau, Taipa, Macao, China.Location evidence
Taipa, MO · Author affiliation
State Key Laboratory of Mechanism and Quality of Chinese Medicine, University of Macau, Taipa, Macao, China.Location evidence
CN · Author affiliation · country only
State Key Laboratory of Mechanism and Quality of Chinese Medicine, University of Macau, Taipa, Macao, China.Location evidence
Chongqing, CN · Author affiliation
Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital) of Third Military Medical University (Army Medical University), Chongqing, China.Location evidence
Shanghai, CN · Author affiliation
Department of Diving and Hyperbaric Medicine, Naval Medical Center, Naval Medical University, Shanghai, China.Location evidence
Shenzhen, CN · Author affiliation
Department of Chemistry and Research Center for Chemical Biology and Omics Analysis, College of Science, Southern University of Science and Technology, Shenzhen, Guangdong, China.Location evidence
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Original abstract
The vacuolar ATPase (V-ATPase) is essential for lysosomal acidification and autophagy, and its activity is regulated by nutrient-sensitive reversible assembly of its V1 and Vo domains. While mTORC1 is known to inhibit V-ATPase assembly, the precise molecular mechanisms remain incompletely understood. Here, using TurboID-based proximity labeling and quantitative mass spectrometry, we identified the R2TP complex subunits RPAP3 and PIH1D1 as novel autophagy-responsive interactors of the V-ATPase V1A subunit (encoded by ATP6V1A). We found that mTORC1 inhibition disrupts the R2TP-V1A interaction, promoting the relocation of the V1 domain to lysosomes and its assembly with the Vo domain to form active proton pumps. Functionally, knockdown of RPAP3 or PIH1D1 enhanced autophagic flux, increased lysosomal proteolytic activity, and promoted the clearance of soluble α-synuclein in a cellular model of Parkinson's disease (PD). Our study reveals the R2TP complex as a critical molecular switch that couples mTORC1 signaling to V-ATPase assembly and lysosomal function, thereby identifying a new pathway for regulating lysosomal catabolism with significant therapeutic potential for neurodegenerative disorders.