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bioRxiv · 10.1101/2024.10.11.617892

Quiescent cell re-entry is limited by macroautophagy-induced lysosomal damage

Murley, A.·Popovici, A.·Hu, X. S.·Lund, A.·Wickham, K.·Durieux, J.·Joe, L.·Koronyo, E.·Dillin, A.
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Abstract

To maintain tissue homeostasis, many cells are kept in a quiescent state until prompted to divide. The re-activation of quiescent cells is perturbed with aging and may underlie declining tissue homeostasis and resiliency. The unfolded protein response regulators IRE-1 and XBP-1 are required for the re-activation of quiescent cells in developmentally L1 arrested C. elegans. Utilizing a forward genetic screen in C. elegans, we discovered that macroautophagy targets protein aggregates to lysosomes in quiescent cells, leading to lysosome damage that prevents cell cycle re-entry in the absence of IRE-1/XBP-1. Genetic inhibition of macroautophagy and stimulation of lysosomes via the overexpression of HLH-30 (TFEB/TFE3) synergistically reduces lysosome damage. Protein aggregates are also targeted to lysosomes by macroautophagy in quiescent cultured mammalian cells, causing lysosome damage that is associated with reduced re-activation. Thus, lysosome damage is a hallmark of quiescent cells and limiting lysosome damage by restraining macroautophagy can stimulate their re-activation.

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Murley, A., Popovici, A., Hu, X. S., Lund, A., Wickham, K., Durieux, J., Joe, L., Koronyo, E., Dillin, A.. 2024-10-13. Quiescent cell re-entry is limited by macroautophagy-induced lysosomal damage. https://doi.org/10.1101/2024.10.11.617892

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