Glyoxalase pathway is required for normal liver-stage proliferation of Plasmodium berghei
Glyoxalase pathway is required for normal liver-stage proliferation of Plasmodium berghei
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DOI：
10.1016/j.bbrc.2021.02.044
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发表时间：
2021-03-02
影响因子：
3.1
通讯作者：
Fukumoto，Shinya
中科院分区：
文献类型：
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作者：
Soga，Akira;Shirozu，Takahiro;Fukumoto，Shinya
乙二醛酶系统是糖酵解的细胞毒性副产物甲基乙二醛的普遍解毒途径。积极增殖的细胞，如癌细胞，依靠它们的能量代谢进行糖酵解。因此，乙二醛酶系统已被评价为抗癌药物的靶点。疟疾孢子子是疟疾寄生虫的感染阶段，在肝细胞中活跃增殖并在2-3天内产生数千个裂殖子。这是感染哺乳动物宿主的第一步。乙二醛酶系统似乎在疟疾寄生虫在肝细胞中的活跃增殖阶段起重要作用。在这项研究中，我们旨在剖析乙二醛酶系统在肝细胞中疟原虫增殖中的作用，以利用反向遗传学方法研究其作为疟疾预防靶点的潜力。疟原虫在胞浆和顶质体中具有由乙二醛酶和gloi样蛋白组成的乙二醛酶系统。我们产生了胞质乙醛酶II（cgloII）敲除、顶质体靶向乙醛酶gloII（tgloII）敲除以及cgloII和tgloII双敲除寄生虫，并对它们进行了表型分析。我们没有观察到gloiiortgloii敲除寄生虫的任何缺陷。相比之下，我们观察到约90%的抑制肝脏期增殖的ggloii和tgloii双敲除寄生虫在体内。这些发现表明，虽然乙醛酶系统是必不可少的，但它在寄生虫在肝细胞中的增殖中起着重要作用。此外，结果表明细胞质和顶质体乙二醛酶途径之间存在互补关系。我们期望寄生虫利用类似于在癌细胞中观察到的系统使其在肝细胞中快速增殖；这一过程可能成为制定预防疟疾的新战略的目标。
The glyoxalase system is a ubiquitous detoxification pathway of methylglyoxal, a cytotoxic byproduct of glycolysis. Actively proliferating cells, such as cancer cells, depend on their energy metabolism for glycolysis. Therefore, the glyoxalase system has been evaluated as a target of anticancer drugs. The malaria sporozoite, which is the infective stage of the malaria parasite, actively proliferates and produces thousands of merozoites within 2–3 days in hepatocytes. This is the first step of infection in mammalian hosts. The glyoxalase system appears to play an important role in this active proliferation stage of the malaria parasite in hepatocytes. In this study, we aimed to dissect the role of the glyoxalase system in malaria parasite proliferation in hepatocytes to examine its potential as a target of malaria prevention using a reverse genetics approach. The malaria parasite possesses a glyoxalase system, comprised of glyoxalases and GloI-like protein, in the cytosol and apicoplast. We generatedcytosolic glyoxalase II(cgloII) knockout, apicoplasttargeted glyoxalase gloII(tgloII)knockout, andcgloIIandtgloIIdouble-knockout parasites and performed their phenotypic analysis. We did not observe any defects in thecgloIIortgloIIknockout parasites. In contrast, we observed approximately 90% inhibition of the liver-stage proliferation ofcgloIIandtgloIIdouble-knockout parasitesin vivo. These findings suggest that although the glyoxalase system is dispensable, it plays an important role in parasite proliferation in hepatocytes. Additionally, the results indicate a complementary relationship between the cytosolic and apicoplast glyoxalase pathways. We expect that the parasite utilizes a system similar to that observed in cancer cells to enable its rapid proliferation in hepatocytes; this process could be targeted in the development of novel strategies to prevent malaria.