Browsing by Author "Sakthivel, Ramanavelan"

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    PK4, a eukaryotic initiation factor 2α(eIF2α) kinase, is essential for the development of the erythrocytic cycle of Plasmodium
    (National Academy of Sciences, 2012) Zhang, Min; Mishra, Satish; Sakthivel, Ramanavelan; Rojas, Margarito; Ranjan, Ravikant; Sullivan, William J., Jr.; Fontoura, Beatriz M. A.; Ménard, Robert; Dever, Thomas E.; Nussenzweig, Victor; Pharmacology and Toxicology, School of Medicine
    In response to environmental stresses, the mammalian serine threonine kinases PERK, GCN2, HRI, and PKR phosphorylate the regulatory serine 51 of the eukaryotic translation initiation factor 2α (eIF2α) to inhibit global protein synthesis. Plasmodium, the protozoan that causes malaria, expresses three eIF2α kinases: IK1, IK2, and PK4. Like GCN2, IK1 regulates stress response to amino acid starvation. IK2 inhibits development of malaria sporozoites present in the mosquito salivary glands. Here we show that the phosphorylation by PK4 of the regulatory serine 59 of Plasmodium eIF2α is essential for the completion of the parasite's erythrocytic cycle that causes disease in humans. PK4 activity leads to the arrest of global protein synthesis in schizonts, where ontogeny of daughter merozoites takes place, and in gametocytes that infect Anopheles mosquitoes. The implication of these findings is that drugs that reduce PK4 activity should alleviate disease and inhibit malaria transmission.
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    The Plasmodium eukaryotic initiation factor-2α kinase IK2 controls the latency of sporozoites in the mosquito salivary glands
    (Rockefeller University Press, 2010) Zhang, Min; Fennell, Clare; Ranford-Cartwright, Lisa; Sakthivel, Ramanavelan; Gueirard, Pascale; Meister, Stephan; Caspi, Anat; Doerig, Christian; Nussenzweig, Ruth S.; Tuteja, Renu; Sullivan, William J., Jr.; Roos, David S.; Fontoura, Beatriz M. A.; Ménard, Robert; Winzeler, Elizabeth A.; Nussenzweig, Victor; Pharmacology and Toxicology, School of Medicine
    Sporozoites, the invasive form of malaria parasites transmitted by mosquitoes, are quiescent while in the insect salivary glands. Sporozoites only differentiate inside of the hepatocytes of the mammalian host. We show that sporozoite latency is an active process controlled by a eukaryotic initiation factor-2alpha (eIF2alpha) kinase (IK2) and a phosphatase. IK2 activity is dominant in salivary gland sporozoites, leading to an inhibition of translation and accumulation of stalled mRNAs into granules. When sporozoites are injected into the mammalian host, an eIF2alpha phosphatase removes the PO4 from eIF2alpha-P, and the repression of translation is alleviated to permit their transformation into liver stages. In IK2 knockout sporozoites, eIF2alpha is not phosphorylated and the parasites transform prematurely into liver stages and lose their infectivity. Thus, to complete their life cycle, Plasmodium sporozoites exploit the mechanism that regulates stress responses in eukaryotic cells.