Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, New Hampshire, United States of America.
PLoS Pathog. 2021 Dec 2;17(12):e1010056. doi: 10.1371/journal.ppat.1010056. eCollection 2021 Dec.
Protozoan parasites continue to cause a significant health and economic burden worldwide. As infectious organisms, they pose unique and difficult challenges due to a level of conservation of critical eukaryotic cellular pathways with their hosts. Gene regulation has been pinpointed as an essential pathway with enough divergence to warrant investigation into therapeutically targeting. Examination of human parasites such as Plasmodium falciparum, Toxoplasma gondii, and kinetoplastids have revealed that epigenetic mechanisms play a key role in their gene regulation. The enzymes involved in adding and removing epigenetic posttranslational modifications (PTMs) have historically been the focus of study. However, the reader proteins that recognize and bind PTMs, initiating recruitment of chromatin-modifying and transcription complexes, are now being realized for their critical role in regulation and their potential as drug targets. In this review, we highlight the current knowledge on epigenetic reader proteins in model parasitic protozoa, focusing on the histone acyl- and methyl-reading domains. With this knowledge base, we compare differences between medically relevant parasites, discuss conceivable functions of these understudied proteins, indicate gaps in knowledge, and provide current progress in drug development.
原生动物寄生虫继续在全球范围内造成重大的健康和经济负担。作为传染性生物体,它们由于与宿主共有的关键真核细胞途径的保守程度而带来独特且困难的挑战。基因调控已被确定为一个必要的途径,其分化程度足以证明值得进行治疗靶向研究。对人类寄生虫(如疟原虫、刚地弓形虫和动基体目原生动物)的研究表明,表观遗传机制在其基因调控中发挥着关键作用。参与添加和去除表观遗传翻译后修饰(PTMs)的酶一直是研究的重点。然而,现在人们意识到识别和结合 PTMs、启动染色质修饰和转录复合物募集的读取蛋白在调节中的关键作用及其作为药物靶点的潜力。在这篇综述中,我们重点介绍了模型寄生原生动物中表观遗传读取蛋白的最新知识,关注组蛋白酰基和甲基读取结构域。基于这一知识库,我们比较了具有医学相关性的寄生虫之间的差异,讨论了这些研究不足的蛋白质的可能功能,指出了知识空白,并提供了药物开发的最新进展。