Gene-dependent yeast cell death pathway requires AP-3 vesicle trafficking leading to vacuole membrane permeabilization

Stolp, Z. D.; Kulkarni, M.; Liu, Y.; Zhu, C.; Jalisi, A.; Lin, S.; Casadevall, A.; Cunningham, K. W.; Pineda, F. J.; Teng, X.; Hardwick, J. M.

doi:10.1101/2021.08.02.454728

bioRxiv · 10.1101/2021.08.02.454728

Gene-dependent yeast cell death pathway requires AP-3 vesicle trafficking leading to vacuole membrane permeabilization

Stolp, Z. D.·Kulkarni, M.·Liu, Y.·Zhu, C.·Jalisi, A.·Lin, S.·Casadevall, A.·Cunningham, K. W.·Pineda, F. J.·Teng, X.·Hardwick, J. M.

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Abstract

Unicellular eukaryotes are suggested to undergo self-inflicted destruction. However, molecular details are sparse by comparison to the mechanisms of cell death known for human cells and animal models. Here we report a molecular pathway in Saccharomyces cerevisiae leading to vacuole/lysosome membrane permeabilization and cell death. Following exposure to heat-ramp conditions, a model of environmental stress, we observed that yeast cell death occurs over several hours, suggesting an ongoing molecular dying process. A genome-wide screen for death-promoting factors identified all subunits of the AP-3 adaptor complex. AP-3 promotes stress-induced cell death through its Arf1-GTPase-dependent vesicle trafficking function, which is required to transport and install proteins on the vacuole/lysosome membrane, including a death-promoting protein kinase Yck3. Time-lapse microscopy revealed a sequence of events where AP-3-dependent vacuole permeability occurs hours before the loss of plasma membrane integrity. An AP-3-dependent cell death pathway appears to be conserved in the human pathogen Cryptococcus neoformans.

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Stolp, Z. D., Kulkarni, M., Liu, Y., Zhu, C., Jalisi, A., Lin, S., Casadevall, A., Cunningham, K. W., Pineda, F. J., Teng, X., Hardwick, J. M.. 2021-08-03. Gene-dependent yeast cell death pathway requires AP-3 vesicle trafficking leading to vacuole membrane permeabilization. https://doi.org/10.1101/2021.08.02.454728

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