Plasmodium falciparum GCN5 plays a key role in regulating artemisinin resistance-related stress responses.
Plasmodium falciparum GCN5 plays a key role in regulating artemisinin resistance-related stress responses.
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DOI：
10.1128/aac.00577-23
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发表时间：
2023-10-18
影响因子：
4.9
通讯作者：
中科院分区：
文献类型：
--
作者：
恶性疟原虫是导致最严重的疟疾的原因，并暴露在人类宿主的各种环境和生理应激中。鉴于GCN5在模式生物的应激反应调节中起着关键作用，我们旨在阐明PfGCN5‘S在恶性疟原虫应激反应中的作用。PfGCN5在热休克、低糖饥饿和青蒿素的活性代谢物双氢青蒿素等三种胁迫条件下显著诱导表达。利用TetR-dozi条件敲除(KD)系统，我们成功地将PfGCN5下调到~50%，发现KD寄生虫对所有三种胁迫条件都变得更加敏感。通过RNA-seq转录分析，在这些胁迫条件下野生型(WT)和KD寄生虫中发现了约1,000个上调和下调基因。重要的是，DHA诱导了许多基因的转录改变，这些基因涉及应激反应的许多方面，在热休克和低糖条件下，这些基因在改变的基因中大量共享，包括与ART抗性相关的基因，如K13和cortin。根据WT和KD寄生虫在三种胁迫条件下的表达模式，约300-400个基因被鉴定参与PfGCN5依赖的、一般的和胁迫条件特异性的反应，三种胁迫条件下的基因高度重叠。值得注意的是，使用环期存活试验，我们发现KD或抑制PfGCN5可以使抗逆转录病毒寄生虫对DHA处理敏感。所有这些都表明，PfGCN5在调节疟疾寄生虫的一般应激反应和ART耐药相关应激反应中起着关键作用，这意味着PfGCN5可能成为疟疾干预的靶标。
Plasmodium falciparum causes the most severe malaria and is exposed to various environmental and physiological stresses in the human host. Given that GCN5 plays a critical role in regulating stress responses in model organisms, we aimed to elucidate PfGCN5’s function in stress responses in P. falciparum. The protein level of PfGCN5 was substantially induced under three stress conditions [heat shock, low glucose starvation, and dihydroartemisinin, the active metabolite of artemisinin (ART)]. With a TetR-DOZI conditional knockdown (KD) system, we successfully down-regulated PfGCN5 to ~50% and found that KD parasites became more sensitive to all three stress conditions. Transcriptomic analysis via RNA-seq identified ~1,000 up- and down-regulated genes in the wild-type (WT) and KD parasites under these stress conditions. Importantly, DHA induced transcriptional alteration of many genes involved in many aspects of stress responses, which were heavily shared among the altered genes under heat shock and low glucose conditions, including ART-resistance-related genes such as K13 and coronin. Based on the expression pattern between WT and KD parasites under three stress conditions, ~300–400 genes were identified to be involved in PfGCN5-dependent, general, and stress-condition-specific responses with high levels of overlaps among three stress conditions. Notably, using ring-stage survival assay, we found that KD or inhibition of PfGCN5 could sensitize the ART-resistant parasites to the DHA treatment. All these indicate that PfGCN5 is pivotal in regulating general and ART-resistance-related stress responses in malaria parasites, implicating PfGCN5 as a potential target for malaria intervention.
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影响因子：
14.9
作者：
Deitsch, KW;Driskill, CL;Wellems, TE
通讯作者：
Wellems, TE
影响因子：
4.9
作者：
Gopalakrishnan, Anusha M.;Kumar, Nirbhay
通讯作者：
Kumar, Nirbhay
影响因子：
4.8
作者：
Day, Jemma;Passecker, Armin;Vakonakis, Ioannis
通讯作者：
Vakonakis, Ioannis
影响因子：
3.7
作者：
Wang J;Huang L;Li J;Fan Q;Long Y;Li Y;Zhou B
通讯作者：
Zhou B
DOI：
10.1126/science.aan6042
发表时间：
2018-03-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Filarsky M;Fraschka SA;Niederwieser I;Brancucci NMB;Carrington E;Carrió E;Moes S;Jenoe P;Bártfai R;Voss TS
通讯作者：
Voss TS