恶性疟原虫组蛋白甲基转移酶PfSET10对于血期寄生虫抗原变异和基因表达的调控是不可或缺的。

IF 3.7 2区 生物学 Q2 MICROBIOLOGY mSphere Pub Date : 2024-11-21 Epub Date: 2024-10-24 DOI:10.1128/msphere.00546-24
Matthias Wyss, Abhishek Kanyal, Igor Niederwieser, Richard Bartfai, Till S Voss
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引用次数: 0

摘要

恶性疟原虫利用毒力因子恶性疟原虫红细胞膜蛋白 1(PfEMP1)的抗原变异来逃避血液感染过程中的适应性免疫反应。PfEMP1 的抗原变异是通过多拷贝变异基因家族各成员互斥表达的表观遗传开关发生的。单个 var 基因的激活与基因座重新定位到核外围的专用区域以及启动子区域组蛋白 3 赖氨酸 4 二/三甲基化(H3K4me2/3)和 H3K9 乙酰化标记的沉积有关。之前的研究发现,推测的 H3K4 特异性甲基转移酶 PfSET10 是变异基因表达的必需酶和正调控因子,但最近的一项研究报告了相互矛盾的数据。在这里,我们利用迭代基因组编辑技术设计了一个条件性 PfSET10 基因敲除品系,以研究 PfSET10 在 var 基因调控中的功能。我们证明,PfSET10 并不是相互排斥的变异基因表达和切换所必需的。我们还发现,PfSET10 不仅对无性寄生虫的增殖是不可或缺的,而且对有性转化和配子细胞分化也是不可或缺的。此外,RNA-seq 比较实验显示,PfSET10 在无性寄生虫发育和配子细胞发生过程中没有明显的基因表达调控作用。但有趣的是,PfSET10 在无性寄生虫和有性寄生虫中显示出不同的核下定位模式,并在成熟配子细胞中显示出雌性特异性表达。总之,我们的工作详细证实了 PfSET10 不参与调节变异基因的表达,也不是血期寄生虫存活所必需的,这表明 PfSET10 可能对蚊媒的生命周期进展或肝脏阶段的发育很重要。为了在人体血液中生存和繁殖,寄生虫需要躲避宿主免疫系统的识别。为此,恶性疟原虫可以通过一种叫做抗原变异的过程来改变表面抗原的表达。这种引人入胜的生存策略是基于变异多基因家族中单个成员表达的不频繁切换。以前的研究报告称,表观遗传调节因子 PfSET10 在控制相互排斥的变异基因表达和切换中的作用存在相互矛盾的结果。在这里,我们明确证明了 PfSET10 既不需要抗原变异,也不需要在血期感染过程中表达任何其他蛋白。这一信息对于引导我们探索控制抗原变异的其他分子机制以及研究 PfSET10 在其他生命周期阶段的功能至关重要。
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The Plasmodium falciparum histone methyltransferase PfSET10 is dispensable for the regulation of antigenic variation and gene expression in blood-stage parasites.

The malaria parasite Plasmodium falciparum employs antigenic variation of the virulence factor P. falciparum erythrocyte membrane protein 1 (PfEMP1) to escape adaptive immune responses during blood infection. Antigenic variation of PfEMP1 occurs through epigenetic switches in the mutually exclusive expression of individual members of the multi-copy var gene family. var genes are located in perinuclear clusters of transcriptionally inactive heterochromatin. Singular var gene activation is linked to locus repositioning into a dedicated zone at the nuclear periphery and deposition of histone 3 lysine 4 di-/trimethylation (H3K4me2/3) and H3K9 acetylation marks in the promoter region. While previous work identified the putative H3K4-specific methyltransferase PfSET10 as an essential enzyme and positive regulator of var gene expression, a recent study reported conflicting data. Here, we used iterative genome editing to engineer a conditional PfSET10 knockout line tailored to study the function of PfSET10 in var gene regulation. We demonstrate that PfSET10 is not required for mutually exclusive var gene expression and switching. We also show that PfSET10 is dispensable not only for asexual parasite proliferation but also for sexual conversion and gametocyte differentiation. Furthermore, comparative RNA-seq experiments revealed that PfSET10 plays no obvious role in regulating gene expression during asexual parasite development and gametocytogenesis. Interestingly, however, PfSET10 shows different subnuclear localization patterns in asexual and sexual stage parasites and female-specific expression in mature gametocytes. In summary, our work confirms in detail that PfSET10 is not involved in regulating var gene expression and is not required for blood-stage parasite viability, indicating PfSET10 may be important for life cycle progression in the mosquito vector or during liver stage development.IMPORTANCEThe malaria parasite Plasmodium falciparum infects hundreds of millions of people every year. To survive and proliferate in the human bloodstream, the parasites need to escape recognition by the host's immune system. To achieve this, P. falciparum can change the expression of surface antigens via a process called antigenic variation. This fascinating survival strategy is based on infrequent switches in the expression of single members of the var multigene family. Previous research reported conflicting results on the role of the epigenetic regulator PfSET10 in controlling mutually exclusive var gene expression and switching. Here, we unequivocally demonstrate that PfSET10 is neither required for antigenic variation nor the expression of any other proteins during blood-stage infection. This information is critical in directing our attention toward exploring alternative molecular mechanisms underlying the control of antigenic variation and investigating the function of PfSET10 in other life cycle stages.

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来源期刊
mSphere
mSphere Immunology and Microbiology-Microbiology
CiteScore
8.50
自引率
2.10%
发文量
192
审稿时长
11 weeks
期刊介绍: mSphere™ is a multi-disciplinary open-access journal that will focus on rapid publication of fundamental contributions to our understanding of microbiology. Its scope will reflect the immense range of fields within the microbial sciences, creating new opportunities for researchers to share findings that are transforming our understanding of human health and disease, ecosystems, neuroscience, agriculture, energy production, climate change, evolution, biogeochemical cycling, and food and drug production. Submissions will be encouraged of all high-quality work that makes fundamental contributions to our understanding of microbiology. mSphere™ will provide streamlined decisions, while carrying on ASM''s tradition for rigorous peer review.
期刊最新文献
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