Rag GTPases Suppress Renal Cystic Disease by Inhibiting TFEB Independently of mTORC1

Area of Science:

• Cell Biology
• Nephrology
• Molecular Medicine

Background:

• Aberrant mTORC1 signaling in renal tubular epithelial cells (rTECs) is linked to renal cystic diseases (RCDs) like ADPKD and TSC.
• The exact role of mTORC1 in RCD pathogenesis remains incompletely understood.
• Rag GTPases are known to recruit mTORC1 to lysosomes for activation.

Purpose of the Study:

• To investigate the precise role of Rag GTPases and mTORC1 in renal cystogenesis.
• To identify key molecular pathways driving cyst formation in RCDs.
• To evaluate potential biomarkers for RCDs.

Main Methods:

• Genetic deletion of RagA/B in mouse rTECs.
• Analysis of mTORC1 activity, TFEB localization, and cystogenesis.
• Comparison of molecular features across different RCD models.

Main Results:

• Deletion of RagA/B in rTECs induced cystogenesis and kidney failure, despite mTORC1 inhibition.
• TFEB was identified as the primary driver of cystogenesis downstream of RagA/B loss.
• Rag GTPases, not mTORC1, were found to be the main in vivo suppressors of TFEB.
• Increased nuclear TFEB was observed in multiple RCD models and is a consistent biomarker in ADPKD.

Conclusions:

• The study challenges the established view that mTORC1 hyperactivation is essential for renal cystogenesis.
• Rag GTPases, through TFEB regulation, play a critical role in suppressing cyst formation.
• Nuclear TFEB may serve as a more reliable biomarker than mTORC1 activity in ADPKD.
• Findings have significant translational implications for RCD treatment strategies.