Spatial Organization of Biological Fuctions | BPS Thematic Meeting

Spatial Organization of Biological Functions Meeting

Poster Abstracts

1-POS Board 1 DECIPHERING THE ROLE OF MICROTUBULE POST-TRANSLATIONAL MODIFICATIONS IN LYSOSOMAL POSITIONING AND FUNCTION USING SUPERRESOLUTION MICROSCOPY Jeganath A 1 ; Nitin Mohan 1 ; 1 Indian Institute of Technology Kanpur, Department of Biological Sciences and Bioengineering, Kanpur, India Lysosomes are central to nutrient signaling and homeostasis. They serve as platforms for two contrasting molecular complexes—mTORC1 (Mechanistic Target of Rapamycin Complex 1), which promotes anabolic growth, and TSC (Tuberous Sclerosis Complex), which supports catabolic recycling. Disruption of this balance can lead to diseases like cancer, diabetes, and obesity. However, how the lysosomes adapt to host these opposing complexes and maintain nutrient homeostasis remains unclear. We focused on studying how lysosomes remodel their physico-chemical properties to host opposing signaling complexes. Emerging evidence links lysosomal positioning to the nutrient state of the cell; under nutrient-rich conditions, when mTORC1 is active, lysosomes localize toward the cell periphery, whereas during nutrient deprivation and mTORC1 inactivation, they cluster near the perinuclear region. Notably, lysosomes engaged in autophagy (low mTORC1 activity) are enriched on detyrosinated microtubules, a specific post-translationally modified microtubule subset. Using the super resolution microscopy techniques, we show that the level of detyrosinated MT decreases under active mTORC1 conditions. Consequently, the active mTORC1-containing lysosomes move fast on the tyrosinated MT. Further, we show that mTORC1 possibly controls tyrosinated/detyrosinated MT levels through S6K1-mediated phosphorylation of the Vasohibin enzyme, which detyrosinates MT. Finally, we establish that mTORC1 activation requires tubulin tyrosination, and modulating the tyrosinated/detyrosinated MT levels can rescue cancer conditions pertaining to mTOR mutations where mTORC1 is hyperactivated. In conclusion, our study reveals a novel avenue in cancer therapeutics targeting lysosomal adaptation (microtubule tyrosination) to recalibrate mTORC1 activity.

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