High Mobility Group Protein HMGB2 Is a Critical Regulator of Plasmodium Oocyst Development

Abstract

The sexual cycle of Plasmodium is required for transmission of malaria from mosquitoes to mammals, but how parasites induce the expression of genes required for the sexual stages is not known. We disrupted the Plasmodium yoelii gene encoding high mobility group nuclear factor hmgb2, which encodes a DNA-binding protein potentially implicated in transcriptional regulation of malaria gene expression. We investigated its function in vivo in the vertebrate and invertebrate hosts. ⌬pyhmgb2 parasites develop into gametocytes but have drastic impairment of oocyst formation. A global transcriptome analysis of the ⌬pyhmgb2 parasites identified ϳ30 genes whose expression is down-regulated in the ⌬pyhmgb2 parasites. These genes are conserved in all malaria species, and more than 90% of these genes show a peak of mRNA expression at the gametocyte stage. Surprisingly, the transcripts coding for the Plasmodium berghei orthologues of those genes are stored and translated in the ookinete stage. Therefore, sexual stage protein expression appears to be both transcriptionally and translationally regulated with Plasmodium HMGB2 acting as an important regulator of malaria sexual stage gene expression.Plasmodium species, the causative agents of malaria, are the most deadly members of the apicomplexan phylum. As with other members of the Apicomplexa, Plasmodium has a multifaceted life cycle encompassing an asexual phase within the intermediate host and a sexual cycle in the mosquito. Gametocytogenesis and gametogenesis consist of an ensemble of processes leading to the differentiation of erythrocytic forms of the parasite into male or female gametocytes. These complex and coordinated steps ensure the transmission of the parasite to the invertebrate host and are required for transmission of malaria to mammalian hosts. Gametocytes form in mammalian host, are taken up by the mosquito during a blood meal, transform into gametes in the mosquito midgut, and then fuse to form a zygote. Zygotes differentiate into ookinetes that penetrate the midgut wall and differentiate into oocysts, in which sporozoites will develop.Starting from the well controlled vertebrate milieu, the parasite must adapt to the mosquito environment where temperature fluctuates and nutrients are limited. Gametocytogenesis requires growth arrest and a differentiation step that will prepare the parasite for these changes. Sexual differentiation is accompanied by a tightly controlled gene expression program during which ϳ200 -300 mRNAs are specifically expressed or predominantly expressed in sexual forms of the parasite (1-4). Transcriptional control of gene expression is implicated as a crucial step during this process with sex-specific transcript expression in gametocytes controlled by the sequences in the 5Ј-flanking regions (5).For some sexual stage genes post-translational processes mediate gene expression. The genes coding for P25 and P28 ookinete proteins (PY00522 and PY00523, respectively) are transcribed at the gametocyte stage, but their translation is delayed unti...

Quantitative Proteomics Reveals New Insights into Erythrocyte Invasion by Plasmodium falciparum

“…[55][56][57][58], and a similar mechanism may act here as well. Equally, high mobility group protein, a nuclear factor that is involved in the modification of histones, has been implicated in playing a role in the transcriptional control of gene expression in the sexual stage of P. yoelii, and it is important in oocyst development in the mosquito (59). Its up-regulation during invasion pathway switching is consistent with the epigenetic regulation of the RH4 locus.…”

Disruption of Parasitehmgb2Gene Attenuates Plasmodium berghei ANKA Pathogenicity

“…*, P Ͻ 0.05; **, P Ͻ 0.01; ***, P Ͻ 0.001. and investigated their growth and their ability to drive ECM in C57BL/6 and BALB/c mice. Few studies have reported gene disruption at the level of erythrocytes in vivo (59)(60)(61). In mice, an absence of the hmgb1 gene is lethal, since hmgb1 Ϫ/Ϫ mice are not viable and die a few hours after birth (62).…”

The Apicomplexan AP2 family: Integral factors regulating Plasmodium development

“…In support of this idea, genome-wide bioinformatic predictions of AP2 domain recognition elements define multiple potential binding sites upstream of virtually all open reading frames [42]. Of course additional DNA binding proteins, some of which have already been identified such as Myb1 (PF13_0088) [63, 64], Myb2 (PF10_0327) [21] and the high mobility group (HMGB) proteins (MAL8P1.72 and PFL0145c) [65, 66], will contribute to the overall picture of transcriptional regulation. In summary, ApiAP2 proteins may function in protein complexes to regulate transcription, and the identification of such complexes will be a key step in unraveling transcription factor-based control of gene expression in Plasmodium .…”