Atg1, a key regulator of autophagy, functions to promote MAPK activation and cell death upon calcium overload in fission yeast.
Atg1, a key regulator of autophagy, functions to promote MAPK activation and cell death upon calcium overload in fission yeast.
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DOI：
10.15698/mic2023.06.798
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发表时间：
2023-06-05
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--
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自噬促进或抑制细胞死亡取决于环境和细胞类型。我们以前的研究结果表明，Atg 1是在基因上参与调节Pmk 1 MAPK在裂殖酵母。在这里，我们发现，在用1，3-β-D-葡聚糖合成酶抑制剂米卡芬净或CaCl 2处理后，Δ atg 1显示出比野生型（WT）细胞更低的Pmk 1 MAPK磷酸化水平，这两种抑制剂都能激活Pmk 1。此外，Atg 1的过量产生，而不是激酶失活Atg 1D 193 A激活Pmk 1没有任何细胞外刺激，表明Atg 1可能促进Pmk 1 MAPK信号转导激活。值得注意的是，Atg 1的过量产生诱导对WT细胞生长的毒性作用，而Pmk 1的缺失未能抑制Atg 1诱导的细胞死亡，表明Atg 1介导的细胞死亡需要Pmk 1激活以外的其他机制。此外，atg 1基因缺失诱导对米卡芬净和CaCl 2的耐受性，而pmk 1缺失诱导对这些化合物的严重敏感性。Δ atg 1 Δ pmk 1双突变体对这些化合物表现出中等敏感性，表明atg 1缺失部分抑制了Δ pmk 1诱导的生长抑制。因此，Atg 1可能会促进米卡芬净和CaCl 2刺激后的细胞死亡，而与Pmk 1 MAPK活性无关。由于米卡芬净和氯化钙是细胞内钙诱导剂，我们的数据揭示了一种新的作用，自噬调节剂Atg 1诱导细胞死亡后，钙超载独立的Pmk 1 MAPK激活的作用。
Autophagy promotes or inhibits cell death depending on the environment and cell type. Our previous findings suggested that Atg1 is genetically involved in the regulation 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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影响因子：
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