Plasmodium falciparum responds to amino acid starvation by entering into a hibernatory state

被引:119
作者
Babbitt, Shalon E. [1 ,2 ,3 ]
Altenhofen, Lindsey [4 ,5 ]
Cobbold, Simon A. [4 ,5 ]
Istvan, Eva S. [1 ,2 ,3 ]
Fennell, Clare [6 ]
Doerig, Christian [6 ,7 ]
Llinas, Manuel [4 ,5 ]
Goldberg, Daniel E. [1 ,2 ,3 ]
机构
[1] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA
[3] Washington Univ, Sch Med, Howard Hughes Med Inst, St Louis, MO 63110 USA
[4] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA
[5] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA
[6] Univ Glasgow, Wellcome Trust Ctr Mol Parasitol, Glasgow G12 8TA, Lanark, Scotland
[7] Monash Univ, Dept Microbiol, Clayton, Vic 3800, Australia
基金
美国国家卫生研究院;
关键词
protease; artemesinin; autophagy; INITIATION FACTOR-2-ALPHA; TRANSCRIPTOME ANALYSIS; LIQUID-CHROMATOGRAPHY; TRANSLATIONAL CONTROL; MALARIA PARASITES; KINASE; GENE; PHOSPHORYLATION; ARTEMISININ; STRESS;
D O I
10.1073/pnas.1209823109
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The human malaria parasite Plasmodium falciparum is auxotrophic for most amino acids. Its amino acid needs are met largely through the degradation of host erythrocyte hemoglobin; however the parasite must acquire isoleucine exogenously, because this amino acid is not present in adult human hemoglobin. We report that when isoleucine is withdrawn from the culture medium of intra-erythrocytic P. falciparum, the parasite slows its metabolism and progresses through its developmental cycle at a reduced rate. Isoleucine-starved parasites remain viable for 72 h and resume rapid growth upon resupplementation. Protein degradation during starvation is important for maintenance of this hibernatory state. Microarray analysis of starved parasites revealed a 60% decrease in the rate of progression through the normal transcriptional program but no other apparent stress response. Plasmodium parasites do not possess a TOR nutrient-sensing pathway and have only a rudimentary amino acid starvation-sensing eukaryotic initiation factor 2 alpha (eIF2 alpha) stress response. Isoleucine deprivation results in GCN2-mediated phosphorylation of eIF2 alpha, but kinase-knockout clones still are able to hibernate and recover, indicating that this pathway does not directly promote survival during isoleucine starvation. We conclude that P. falciparum, in the absence of canonical eukaryotic nutrient stress-response pathways, can cope with an inconsistent bloodstream amino acid supply by hibernating and waiting for more nutrient to be provided.
引用
收藏
页码:E3278 / E3287
页数:10
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