Abstract
15-Deoxyspergualin, an immunosuppressant with tumoricidal and antimalarial properties, has been implicated in the inhibition of a diverse array of cellular processes including polyamine synthesis and protein synthesis. Endeavoring to identify the mechanism of antimalarial action of this molecule, we examined its effect on Plasmodium falciparum protein synthesis, polyamine biosynthesis, and transport. 15-Deoxyspergualin stalled protein synthesis in P. falciparum through Hsp70 sequestration and subsequent phosphorylation of the eukaryotic initiation factor eIF2alpha. However, protein synthesis inhibition as well as polyamine depletion were invoked only by high micromolar concentrations of 15-deoxyspergualin, in contrast to the submicromolar concentrations sufficient to inhibit parasite growth. Further investigations demonstrated that 15-deoxyspergualin in the malaria parasite primarily targets the hitherto underexplored process of trafficking of nucleus-encoded proteins to the apicoplast. Our finding that 15-deoxyspergualin kills the malaria parasite by interfering with targeting of nucleus-encoded proteins to the apicoplast not only exposes a chink in the armor of the malaria parasite, but also reveals new realms in our endeavors to study this intriguing biological process.
Highlights
(DFMO) are known to be incapable of suppressing malaria in infected mice [2]
The heme-regulated eIF2␣ kinase, HRI, is normally maintained in an inactive, unphosphorylated form by association with Hsp70 [9], and we recently demonstrated that sequestration of heat shock proteins by DSG in mammalian cells leads to protein synthesis inhibition and cell death through autophosphorylation of HRI and subsequent phosphorylation of eIF2␣ [10]
A heme-regulated eIF2␣ kinase akin to the mammalian HRI is known to exist in Plasmodium falciparum, and Surolia and Padmanaban have earlier demonstrated that the autophosphorylation of this eIF2␣ kinase and the subsequent phosphorylation of eIF2␣ in P. falciparum can bring about protein synthesis inhibition and parasite death [11, 12]
Summary
Proteins to the apicoplast by this molecule, which we describe here. Plasmodium and other members of the protozoan group Apicomplexa are characterized by the presence of a four-membrane relict plastid, the apicoplast acquired by secondary endosymbiosis [13,14,15]. The apicoplast is essential to parasite survival [27], and its elimination by pharmacological or molecular genetic manipulation has been demonstrated to evoke distinctive delayed death kinetics, an intriguing biological phenomenon characterized by normal parasite growth in the host cell immediately following apicoplast perturbation, but parasite death subsequent to the invasion of a new host cell [28, 29]. This phenomenon has been rationalized as the consequence of the generation of daughter cells devoid of apicoplast following missegregation of the apicoplast because of inhibition of an apicoplast function [28]. Our somewhat serendipitous finding that a widely used small molecule, 15-deoxyspergualin, kills the malaria parasite by disrupting targeting of NEAT proteins to the apicoplast, provides new opportunities to study this interesting biological process as well as opens up possibilities of developing inhibitors of this process as antimalarial agents
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