Inhibiting the Plasmodium eIF2α Kinase PK4 Prevents Artemisinin-Induced Latency.
Inhibiting the Plasmodium eIF2α Kinase PK4 Prevents Artemisinin-Induced Latency.
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DOI：
10.1016/j.chom.2017.11.005
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发表时间：
2017-12-13
影响因子：
30.3
通讯作者：
Sullivan WJ Jr
中科院分区：
文献类型：
--
作者：
Zhang M;Gallego-Delgado J;Fernandez-Arias C;Waters NC;Rodriguez A;Tsuji M;Wek RC;Nussenzweig V;Sullivan WJ Jr
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. The antimalarial drug artemisinin is associated with a high frequency of recrudescent infection. Zhang et al. identified that artemisinin induces latency through Plasmodium eukaryotic initiation factor 2α (eIF2α) phosphorylation. Inhibiting the Plasmodium eIF2α kinase PK4 blocks parasites from entering latency and abolishes recrudescence after artemisinin therapy.
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影响因子：
3
作者：
Li Q;Remich S;Miller SR;Ogutu B;Otieno W;Melendez V;Teja-Isavadharm P;Weina PJ;Hickman MR;Smith B;Polhemus M
通讯作者：
Polhemus M
影响因子：
0.8
作者：
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通讯作者：
Assallum, Hussein
影响因子：
64.8
作者：
Eckstein-Ludwig, U;Webb, RJ;Krishna, S
通讯作者：
Krishna, S
DOI：
10.1073/pnas.1217452110
发表时间：
2013-03-26
影响因子：
11.1
作者：
Klonis, Nectarios;Xie, Stanley C.;Tilley, Leann
通讯作者：
Tilley, Leann
影响因子：
16.6
作者：
Chen MZ;Moily NS;Bridgford JL;Wood RJ;Radwan M;Smith TA;Song Z;Tang BZ;Tilley L;Xu X;Reid GE;Pouladi MA;Hong Y;Hatters DM
通讯作者：
Hatters DM