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Teruaki Takasaki1, Ryosuke Utsumi1, Erika Shimada1, Asuka Bamba1, Kanako Hagihara2, Ryosuke Satoh1, and Reiko Sugiura1

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Autophagy promotes or inhibits cell death depending on the environment and cell type. Our previous findings suggested that Atg1 is genetically involved in the regula-tion of Pmk1 MAPK in fission yeast. Here, we showed that Δatg1 displays lower levels of Pmk1 MAPK phosphorylation than did the wild-type (WT) cells upon treatment with a 1,3-β-D-glucan synthase inhibitor micafungin or CaCl2, both of which activate Pmk1. Moreover, the overproduction of Atg1, but not that of the kinase inactivating Atg1D193A activates Pmk1 without any extracellular stimuli, suggesting that Atg1 may promote Pmk1 MAPK signaling activation. Notably, the overproduction of Atg1 induces a toxic effect on the growth of WT cells and the deletion of Pmk1 failed to suppress the cell death induced by Atg1, indicating that the Atg1-mediated cell death requires additional mechanism(s) other than Pmk1 activation. Moreover, atg1 gene deletion induces tolerance to micafungin and CaCl2, whereas pmk1 deletion induces severe sensitivities to these compounds. The Δatg1Δpmk1 double mutants display intermediate sensitivities to these compounds, showing that atg1 deletion partly suppressed growth inhibition induced by Δpmk1. Thus, Atg1 may act to promote cell death upon micafungin and CaCl2 stimuli regardless of Pmk1 MAPK activity. Since micafungin and CaCl2 are intracellular calcium inducers, our data reveal a novel role of the autophagy regulator Atg1 to induce cell death upon calcium overload independent of its role in Pmk1 MAPK activation.

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ACKNOWLEDGMENTS

We thank Dr. Mohan K. Balasubramanian for providing the atg1 knockout strain, Dr. Kaoru Takegawa for providing the strains lacking autophagy-related genes, and the members of Sugiura Lab for discussion and technical support. This study was supported by the MEXT‐Supported Program for the Strategic Research Foundation at Private Universities, 2014–2018 (S1411037), and by JSPS KAKENHI Grant Numbers 20K07058 (T. Takasaki), JP20K06494 (R. Satoh), JPS1411037 (R. Sugiura). This work was also supported by a grant by the Antiaging Project for Private Universities (R. Sugiura).

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Atg1, a key regulator of autophagy, functions to promote MAPK activation and cell death upon calcium overload in fission yeast by Takasaki et al. is licensed under a Creative Commons Attribution 4.0 International License.