Department of Cell Biology, University of Alberta, Edmonton, Canada.
Department of Cell Biology, University of Alberta, Edmonton, Canada
Life Sci Alliance. 2019 Jul 24;2(4). doi: 10.26508/lsa.201900421. Print 2019 Aug.
Trypanosomatid parasites are infectious agents for diseases such as African sleeping sickness, Chagas disease, and leishmaniasis that threaten millions of people, mostly in the emerging world. Trypanosomes compartmentalize glycolytic enzymes to an organelle called the glycosome, a specialized peroxisome. Functionally intact glycosomes are essential for trypanosomatid viability, making glycosomal proteins as potential drug targets against trypanosomatid diseases. Peroxins (Pex), of which Pex3 is the master regulator, control glycosome biogenesis. Although Pex3 has been found throughout the eukaryota, its identity has remained stubbornly elusive in trypanosomes. We used bioinformatics predictive of protein secondary structure to identify trypanosomal Pex3. Microscopic and biochemical analyses showed trypanosomal Pex3 to be glycosomal. Interaction of Pex3 with the peroxisomal membrane protein receptor Pex19 observed for other eukaryotes is replicated by trypanosomal Pex3 and Pex19. Depletion of Pex3 leads to mislocalization of glycosomal proteins to the cytosol, reduced glycosome numbers, and trypanosomatid death. Our findings are consistent with being an essential gene in trypanosomes.
锥虫类寄生虫是引起非洲昏睡病、恰加斯病和利什曼病等疾病的病原体，这些疾病威胁着全球数百万人的生命，其中大多数生活在新兴世界。锥虫将糖酵解酶分隔到一个叫做糖体的细胞器中，这是一种特殊的过氧化物酶体。功能完整的糖体对于锥虫的生存至关重要，因此糖体蛋白成为针对锥虫病的潜在药物靶点。过氧化物酶体（Pex），其中 Pex3 是主要调节因子，控制糖体的生物发生。尽管 Pex3 在真核生物中被广泛发现，但在锥虫中其身份仍然难以捉摸。我们使用预测蛋白质二级结构的生物信息学方法来鉴定锥虫 Pex3。显微镜和生化分析表明，锥虫 Pex3 存在于糖体中。与其他真核生物中观察到的过氧化物酶体膜蛋白受体 Pex19 的相互作用在锥虫 Pex3 和 Pex19 中得到了复制。Pex3 的耗竭导致糖体蛋白向细胞质的定位错误、糖体数量减少和锥虫死亡。我们的发现与 Pex3 是锥虫中必需的基因相一致。
