Division of Cellular and Applied Infection Biology, Institute of Zoology, RWTH Aachen University, Aachen, Germany.
Core Facility for Mass Spectrometry, Institute of Immunology, University Medical Centre of the Johannes-Gutenberg University, Mainz, Germany.
Mol Microbiol. 2024 Mar;121(3):543-564. doi: 10.1111/mmi.15215. Epub 2023 Dec 26.
The transmission of malaria parasites to mosquitoes is dependent on the formation of gametocytes. Once fully matured, gametocytes are able to transform into gametes in the mosquito's midgut, a process accompanied with their egress from the enveloping erythrocyte. Gametocyte maturation and gametogenesis require a well-coordinated gene expression program that involves a wide spectrum of regulatory proteins, ranging from histone modifiers to transcription factors to RNA-binding proteins. Here, we investigated the role of the CCCH zinc finger protein MD3 in Plasmodium falciparum gametocytogenesis. MD3 was originally identified as an epigenetically regulated protein of immature gametocytes and recently shown to be involved in male development in a barcode-based screen in P. berghei. We report that MD3 is mainly present in the cytoplasm of immature male P. falciparum gametocytes. Parasites deficient of MD3 are impaired in gametocyte maturation and male gametocytogenesis. BioID analysis in combination with co-immunoprecipitation assays unveiled an interaction network of MD3 with RNA-binding proteins like PABP1 and ALBA3, with translational initiators, regulators and repressors like elF4G, PUF1, NOT1 and CITH, and with further regulators of gametocytogenesis, including ZNF4, MD1 and GD1. We conclude that MD3 is part of a regulator complex crucial for post-transcriptional fine-tuning of male gametocytogenesis.
疟原虫向蚊子传播依赖于配子体的形成。一旦完全成熟，配子体就能够在蚊子的中肠转化为配子，这一过程伴随着它们从被包裹的红细胞中逸出。配子体的成熟和配子发生需要一个协调良好的基因表达程序，涉及广泛的调节蛋白，从组蛋白修饰酶到转录因子到 RNA 结合蛋白。在这里，我们研究了 CCCH 锌指蛋白 MD3 在恶性疟原虫配子发生中的作用。MD3 最初被鉴定为未成熟配子体的表观遗传调节蛋白，最近在 P. berghei 的基于条码的筛选中显示参与雄性发育。我们报告说，MD3 主要存在于未成熟的恶性疟原虫雄性配子体的细胞质中。缺乏 MD3 的寄生虫在配子体成熟和雄性配子发生中受损。BioID 分析结合共免疫沉淀实验揭示了 MD3 与 RNA 结合蛋白（如 PABP1 和 ALBA3）、翻译起始因子（如 elF4G、PUF1、NOT1 和 CITH）以及配子发生的其他调节剂（包括 ZNF4、MD1 和 GD1）之间的相互作用网络。我们得出结论，MD3 是一个对雄性配子发生的转录后精细调控至关重要的调节复合物的一部分。
