PfeIK1, a eukaryotic initiation factor 2α kinase of the human malaria parasite Plasmodium falciparum, regulates stress-response to amino-acid starvation

Fennell, Clare; Babbitt, Shalon E.; Russo, Ilaria; Wilkes, Jonathan M.; Ranford-Cartwright, Lisa; Goldberg, Daniel E.; Doerig, Christian

doi:10.1186/1475-2875-8-99

Cited by 92 publications

(111 citation statements)

References 44 publications

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“…For example, a GCN2-like kinase has been identified that is also present in A. locustae, another insect microsporidia. GCN2p is involved in eiF2α phosphorylation, leading to translation inhibition in nutrient starvation conditions in yeast 39 as well as in other intracellular eukaryotic parasites [40][41][42] . Furthermore, Ste20 and Ste11 belonging to the MAPKKK pathway were also identified.…”

Section: Discussionmentioning

confidence: 99%

Annotation of microsporidian genomes using transcriptional signals

et al. 2012

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High-quality annotation of microsporidian genomes is essential for understanding the biological processes that govern the development of these parasites. Here we present an improved structural annotation method using transcriptional DnA signals. We apply this method to re-annotate four previously annotated genomes, which allow us to detect annotation errors and identify a significant number of unpredicted genes. We then annotate the newly sequenced genome of Anncaliia algerae. A comparative genomic analysis of A. algerae permits the identification of not only microsporidian core genes, but also potentially highly expressed genes encoding membrane-associated proteins, which represent good candidates involved in the spore architecture, the invasion process and the microsporidianhost relationships. Furthermore, we find that the ten-fold variation in microsporidian genome sizes is not due to gene number, size or complexity, but instead stems from the presence of transposable elements. such elements, along with kinase regulatory pathways and specific transporters, appear to be key factors in microsporidian adaptive processes.

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Section: Discussionmentioning

confidence: 99%

Annotation of microsporidian genomes using transcriptional signals

et al. 2012

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“…This approach culminated in a kinome-wide study demonstrating that 23 P. berghei ePKs are redundant for asexual erythrocytic parasite development in mice and identifying phenotypes in sexual development for a number of these 23 ePKs [51]. A similar strategy in P. falciparum identified roles for an orphan kinase in proliferation rate linked to the number of progeny merozoites per schizont [36], for an eIF2a kinase in response to starvation stress, similar to GCN2, its closest homologue in yeast [52], and for CDPKs in motility during invasion [53] or egress of merozoites from the erythrocyte [54], to cite a few specific studies; more recently, a kinome-wide approach [19] identified 36 ePKs as refractory to gene disruption, and thus as likely crucial players in asexual proliferation in erythrocytes.…”

Section: E C To C a R P U S S Il Ic U Lo S U S T H A L A S S I O S I mentioning

confidence: 99%

An evolutionary perspective on the kinome of malaria parasites

Talevich

Tobin

Kannan

et al. 2012

Phil. Trans. R. Soc. B

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Malaria parasites belong to an ancient lineage that diverged very early from the main branch of eukaryotes. The approximately 90-member plasmodial kinome includes a majority of eukaryotic protein kinases that clearly cluster within the AGC, CMGC, TKL, CaMK and CK1 groups found in yeast, plants and mammals, testifying to the ancient ancestry of these families. However, several hundred millions years of independent evolution, and the specific pressures brought about by first a photosynthetic and then a parasitic lifestyle, led to the emergence of unique features in the plasmodial kinome. These include taxon-restricted kinase families, and unique peculiarities of individual enzymes even when they have homologues in other eukaryotes. Here, we merge essential aspects of all three malaria-related communications that were presented at the Evolution of Protein Phosphorylation meeting, and propose an integrated discussion of the specific features of the parasite's kinome and phosphoproteome.

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“…In P. falciparum, exposure to amino acid-free RPMI results in the phosphorylation of parasite eIF2α (PfeIF2α) (15). Considering that isoleucine is the only amino acid for which the parasite can truly be starved, we examined the specificity of this response.…”

Section: Isoleucine-starved Parasites Have Reduced Levels Of Central-mentioning

confidence: 99%

“…Plasmodium does not have a TOR complex (14) and lacks the downstream transcription factors and biosynthetic pathways that mediate GCN2 action. An ortholog of eIF2α and three putative eIF2α kinases have been identified previously in the P. falciparum genome (15)(16)(17). One of them, PfeIK2, controls latency in sporozoite development in the mosquito (17).…”

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confidence: 99%

“…Another, PfPK4, is involved in intraerythrocytic schizogony (18). The third, PfeIK1, recently has been confirmed as the amino acid-sensing GCN2 ortholog, active in the blood stages of the parasite and able to phosphorylate eIF2α in response to amino acid starvation (15). A knockout of GCN2 in the related apicomplexan parasite Toxoplasma gondii has an extracellular tachyzoite fitness defect (19), but the biological role of the Plasmodium ortholog has not been defined and is tenuous, given the lack of GCN2-responsive transcription factors and amino acid biosynthesis pathways.…”

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confidence: 99%

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

Babbitt

Altenhofen

Cobbold

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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153

242

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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 intraerythrocytic 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 2α (eIF2α) stress response. Isoleucine deprivation results in GCN2-mediated phosphorylation of eIF2α, 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.protease | artemesinin | autophagy

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PfeIK1, a eukaryotic initiation factor 2α kinase of the human malaria parasite Plasmodium falciparum, regulates stress-response to amino-acid starvation

Cited by 92 publications

References 44 publications

Annotation of microsporidian genomes using transcriptional signals

Annotation of microsporidian genomes using transcriptional signals

An evolutionary perspective on the kinome of malaria parasites

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

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