Yeast cell death pathway requiring AP-3 vesicle trafficking leads to vacuole/lysosome membrane permeabilization.
Yeast cell death pathway requiring AP-3 vesicle trafficking leads to vacuole/lysosome membrane permeabilization.
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DOI：
10.1016/j.celrep.2022.110647
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发表时间：
2022-04-12
期刊：
影响因子：
8.8
通讯作者：
Hardwick, J. Marie
中科院分区：
文献类型：
--
作者：
Stolp, Zachary D.;Kulkarni, Madhura;Liu, Yining;Zhu, Chengzhang;Jalisi, Alizay;Lin, Si;Casadevall, Arturo;Cunningham, Kyle W.;Pineda, Fernando J.;Teng, Xinchen;Hardwick, J. Marie
单细胞真核生物被认为正在经历自我毁灭。然而，与人类细胞和动物模型中已知的程序性/调节性细胞死亡机制相比，分子细节较少。在这里，我们报道了酿酒酵母中导致液泡/溶酶体膜渗透的分子细胞死亡途径。在短暂的细胞死亡刺激后，酵母细胞在几个小时内缓慢死亡，与正在进行的分子死亡过程一致。全基因组筛选死亡促进因子确定了AP-3复合物的所有亚基，AP-3复合物是一种囊泡运输适配器，已知用于在液泡/溶酶体膜上运输和安装新合成的蛋白质。为了促进细胞死亡，AP-3需要其arf1 - gtpase依赖的囊泡运输功能和激酶Yck3，后者通过AP-3选择性地转运到液泡膜上。视频显微镜显示液泡渗透性先于质膜完整性丧失的一系列事件。ap -3依赖性死亡在人致病性酵母新隐球菌中似乎是保守的。哺乳动物细胞如何死亡的细节已经产生了有效的癌症治疗方法。同样，真菌细胞死亡的细节可以解释抗真菌药物的失败反应，并为下一代抗真菌策略提供信息。Stolp等人描述了酵母细胞死亡颠覆的潜在机制，通过抑制AP-3囊泡运输来阻断液泡/溶酶体的渗透性。
Unicellular eukaryotes have been suggested as undergoing self-inflicted destruction. However, molecular details are sparse compared with the mechanisms of programmed/regulated cell death known for human cells and animal models. Here, we report a molecular cell death pathway in Saccharomyces cerevisiae leading to vacuole/lysosome membrane permeabilization. Following a transient cell death stimulus, yeast cells die slowly over several hours, consistent with an ongoing molecular dying process. A genome-wide screen for death-promoting factors identified all subunits of the AP-3 complex, a vesicle trafficking adapter known to transport and install newly synthesized proteins on the vacuole/lysosome membrane. To promote cell death, AP-3 requires its Arf1-GTPase-dependent vesicle trafficking function and the kinase Yck3, which is selectively transported to the vacuole membrane by AP-3. Video microscopy revealed a sequence of events where vacuole permeability precedes the loss of plasma membrane integrity. AP-3-dependent death appears to be conserved in the human pathogenic yeast Cryptococcus neoformans. Details about how mammalian cells die have yielded effective cancer therapies. Similarly, details about fungal cell death may explain failed responses to anti-fungal agents and inform next-generation anti-fungal strategies. Stolp et al. describe a potential mechanism of yeast cell death subversion, by inhibiting AP-3 vesicle trafficking to block vacuole/lysosome permeability.
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作者：
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发表时间：
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期刊：
Science (New York, N.Y.)
影响因子：
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DOI：
10.1073/pnas.2004876117
发表时间：
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影响因子：
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