Protein KIC5 is a novel regulator of artemisinin stress response in the malaria parasite Plasmodium falciparum.
Protein KIC5 is a novel regulator of artemisinin stress response in the malaria parasite Plasmodium falciparum.
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DOI：
10.1038/s41598-023-27417-6
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发表时间：
2023-01-09
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
青蒿素综合疗法已导致恶性疟原虫疟疾死亡率大幅下降。这一进展现在受到新出现的青蒿素耐药性（ART-R）的威胁，这种耐药性最初在东南亚与Kelch螺旋桨蛋白（K13）的多态性有关，最近又与其他几种看似无关的基因突变有关。为了更好地了解寄生虫对ART的反应，我们正在表征通过piggyBac转座子诱变产生的对ART敏感性改变的恶性疟原虫突变体。转座子插入到一个基因的假定转录起始位点附近，该基因被定义为“功能未知的疟原虫保守基因”，现在作为Kelch 13相互作用候选5蛋白（KIC 5）与K13功能性连接。红细胞内无性发育过程中KIC 5突变体的表型分析确定了与DNA应激反应和线粒体代谢改变相关的转录变化，将KIC 5基因的失调与寄生虫对ART暴露的反应能力联系起来。通过对KIC 5转录组的表征，我们假设该基因在ART暴露下可能是必需的，以在早期环阶段管理野生型应激反应的基因表达，从而更好地了解寄生虫的过程，可以改变ART敏感性。
Artemisinin combination therapies (ACTs) have led to a significant decrease in Plasmodium falciparum malaria mortality. This progress is now threatened by emerging artemisinin resistance (ART-R) linked originally in SE Asia to polymorphisms in the Kelch propeller protein (K13) and more recently to several other seemingly unrelated genetic mutations. To better understand the parasite response to ART, we are characterizing a P. falciparum mutant with altered sensitivity to ART that was created via piggyBac transposon mutagenesis. The transposon inserted near the putative transcription start site of a gene defined as a “Plasmodium-conserved gene of unknown function,” now functionally linked to K13 as the Kelch13 Interacting Candidate 5 protein (KIC5). Phenotype analysis of the KIC5 mutant during intraerythrocytic asexual development identified transcriptional changes associated with DNA stress response and altered mitochondrial metabolism, linking dysregulation of the KIC5 gene to the parasite’s ability to respond to ART exposure. Through characterization of the KIC5 transcriptome, we hypothesize that this gene may be essential under ART exposure to manage gene expression of the wild-type stress response at early ring stage, thereby providing a better understanding of the parasite’s processes that can alter ART sensitivity.
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影响因子：
16.6
作者：
Mok S;Stokes BH;Gnädig NF;Ross LS;Yeo T;Amaratunga C;Allman E;Solyakov L;Bottrill AR;Tripathi J;Fairhurst RM;Llinás M;Bozdech Z;Tobin AB;Fidock DA
通讯作者：
Fidock DA
影响因子：
9.8
作者：
Bozdech, Zbynek;Llinas, Manuel;Pulliam, Brian Lee;Wong, Edith D;Zhu, Jingchun;DeRisi, Joseph L
通讯作者：
DeRisi, Joseph L
影响因子：
4.4
作者：
Gibbons J;Button-Simons KA;Adapa SR;Li S;Pietsch M;Zhang M;Liao X;Adams JH;Ferdig MT;Jiang RHY
通讯作者：
Jiang RHY
DOI：
10.1073/pnas.1104063108
发表时间：
2011-07-12
影响因子：
11.1
作者：
Klonis, Nectarios;Crespo-Ortiz, Maria P.;Tilley, Leann
通讯作者：
Tilley, Leann
影响因子：
6.7
作者：
Gnadig, Nina F.;Stokes, Barbara H.;Fidock, David A.
通讯作者：
Fidock, David A.