Browsing by Author "Nussenzweig, Victor"

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    Inhibiting the Plasmodium eIF2α Kinase PK4 Prevents Artemisinin-Induced Latency
    (Elsevier, 2017-12) Zhang, Min; Gallego-Delgado, Julio; Fernandez-Arias, Cristina; Waters, Norman C.; Rodriguez, Ana; Tsu, Moriya; Wek, Ronald C.; Nussenzweig, Victor; Sullivan, William J., Jr.; Pharmacology and Toxicology, School of Medicine
    Artemisinin and its derivatives (ARTs) are frontline antimalarial drugs. However, ART monotherapy is associated with a high frequency of recrudescent infection, resulting in treatment failure. A subset of parasites is thought to undergo ART-induced latency, but the mechanisms remain unknown. Here, we report that ART treatment results in phosphorylation of the parasite eukaryotic initiation factor-2α (eIF2α), leading to repression of general translation and latency induction. Enhanced phosphorylated eIF2α correlates with high rates of recrudescence following ART, and inhibiting eIF2α dephosphorylation renders parasites less sensitive to ART treatment. ART-induced eIF2α phosphorylation is mediated by the Plasmodium eIF2α kinase, PK4. Overexpression of a PK4 dominant-negative or pharmacological inhibition of PK4 blocks parasites from entering latency and abolishes recrudescence after ART treatment of infected mice. These results show that translational control underlies ART-induced latency and that interference with this stress response may resolve the clinical problem of recrudescent infection.
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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.
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    Translational Control in Plasmodium and Toxoplasma Parasites
    (American Society for Microbiology, 2013) Zhang, Min; Joyce, Bradley R.; Sullivan, William J., Jr.; Nussenzweig, Victor; Pharmacology and Toxicology, School of Medicine
    The life cycles of apicomplexan parasites such as Plasmodium spp. and Toxoplasma gondii are complex, consisting of proliferative and latent stages within multiple hosts. Dramatic transformations take place during the cycles, and they demand precise control of gene expression at all levels, including translation. This review focuses on the mechanisms that regulate translational control in Plasmodium and Toxoplasma, with a particular emphasis on the phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α). Phosphorylation of eIF2α (eIF2α∼P) is a conserved mechanism that eukaryotic cells use to repress global protein synthesis while enhancing gene-specific translation of a subset of mRNAs. Elevated levels of eIF2α∼P have been observed during latent stages in both Toxoplasma and Plasmodium, indicating that translational control plays a role in maintaining dormancy. Parasite-specific eIF2α kinases and phosphatases are also required for proper developmental transitions and adaptation to cellular stresses encountered during the life cycle. Identification of small-molecule inhibitors of apicomplexan eIF2α kinases may selectively interfere with parasite translational control and lead to the development of new therapies to treat malaria and toxoplasmosis.