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bioRxiv · 10.64898/2025.12.23.696270

Compromised ESCRT signalling is sufficient for resistance to the Target of Rapamycin Complex inhibitor Torin1 in fission yeast

Alao, J. P.·Islam, R. A.·Toyoda, Y.·Saitoh, S.·Rallis, C.
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Abstract

BackgroundFission yeast cells defective in Golgi-endosomal sorting display high resistance to Torin1, a pan-Target of Rapamycin (TOR) inhibitor. TOR complexes regulate the ESCRT system to integrate nutrient availability with cell division. TOR activity is frequently deregulated in cancer, making it an attractive therapeutic target. Deregulated ESCRT activity has also been associated with cancer, but its role in mediating drug resistance is not fully understood. Herein, we have investigated the role of the ESCRT system in regulating sensitivity to Torin1. MethodsGrowth assays were used to monitor the growth of yeast cells. The effect of Torin1 on protein expression was monitored by immunoblotting. Fluorescence microscopy was used to investigate the action of Torin1 on protein localization. ResultsThe ESCRT system mediates Torin1-induced degradation of amino acid and glucose transporters. The expression of these transporters at the plasma membrane is not abolished in ESCRT mutants. Mutants unable to effectively ubiquitylate these transporters are also resistant to Torin1. Impaired ESCRT-mediated protein degradation is associated with strong resistance to Torin1. ConclusionsMutations in genes encoding ESCRT components have been reported in cancer. We present evidence that compromised ESCRT signalling is sufficient for resistance to Torin1. Cells defective in ESCRT signalling or ubiquitin homeostasis are highly resistant to Torin1. Our studies demonstrate that defective ESCRT-mediated proteolysis can suppress sensitivity to Torin1.

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Alao, J. P., Islam, R. A., Toyoda, Y., Saitoh, S., Rallis, C.. 2025-12-25. Compromised ESCRT signalling is sufficient for resistance to the Target of Rapamycin Complex inhibitor Torin1 in fission yeast. https://doi.org/10.64898/2025.12.23.696270

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