mTORC1 signaling modulate microtubule tyrosination/detyrosination status to regulate lysosome dynamics

Abstract Lysosomes integrate nutrient sensing and metabolic signaling by dynamically repositioning within the cytoplasm. While motors and lysosomal surface adaptors driving this movement are well studied, how the microtubule cytoskeleton specifies lysosomal transport and its coupling to mechanistic target of rapamycin complex 1 (mTORC1) signaling remains unclear. Here, we show that tubulin post-translational modifications (PTMs) define the tracks that guide nutrient-responsive lysosome positioning. Using super-resolution imaging and biochemical assays, we demonstrate that lysosomes carrying active mTORC1 preferentially traffic along tyrosinated microtubules to reach the cell periphery, whereas detyrosinated microtubules restrict their motility. Nutrient stimulation enhances this outward transport, while concurrently suppressing microtubule detyrosination through mTORC1-S6K1 signaling, likely via inhibition of vasohibin activity. This ensures selective expansion of tyrosinated microtubule tracks to sustain mTORC1 signaling. Strikingly, in cancer cells where aberrant mTORC1 activity correlates with altered microtubule tyrosination, restoring microtubule detyrosination rescues mTORC1 hyperactivation and suppresses cell migration and epithelial-to-mesenchymal transition. Thus, demonstrating that tubulin post-translational modifications (PTMs) define the tracks that guide the positioning of nutrient-responsive lysosomes. These findings uncover a crosstalk between mTORC1 and tubulin tyrosination/detyrosination status that couples nutrient availability to lysosomal dynamics and identify microtubule tyrosination as a regulatory node with therapeutic potential in cancer.