Replication and partitioning of the apicoplast genome of Toxoplasma gondii is linked to the cell cycle and requires DNA polymerase and gyrase

Martins‐Duarte, Erica S.; Sheiner, Lilach; Reiff, Sarah B.; Souza, Wanderley de; Striepen, Boris

doi:10.1016/j.ijpara.2020.11.004

Cited by 13 publications

(5 citation statements)

References 79 publications

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“…The most highly enriched PfHO-specific interactor in both IP/MS experiments was an unannotated protein (Pf3D7_1025300) that contains a putative aspartyl protease domain and shows distant structural similarity to DNA damage-inducible protein (Ddi-1, P40087) -a ubiquitin-dependent protease associated with transcription factor processing [59][60][61] (Figure 5 -figure supplement 2). These putative interactors are consistent with reports of non-canonical HO roles in gene expression [62][63][64] , retention by mature PfHO of an electropositive N-terminus favorable for interacting with nucleic acids (Figure 4B), and apparent PfHO localization to the membrane periphery of the apicoplast lumen (Figure 3B) where the apicoplast genome, DNA replication factors, and ribosomes associate [65][66][67] . We thus considered it most likely that PfHO had an essential function in either apicoplast genome replication or DNA-dependent gene expression.…”

Section: Figure Supplement 1 Sequence Homologs Of Pfho Based On Blastsupporting

confidence: 89%

Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis

Blackwell,

Jami-Alahmadi,

Nasamu

et al. 2024

Preprint

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Malaria parasites have evolved unusual metabolic adaptations that specialize them for growth within heme-rich human erythrocytes. During blood-stage infection,Plasmodium falciparumparasites internalize and digest abundant host hemoglobin within the digestive vacuole. This massive catabolic process generates copious free heme, most of which is biomineralized into inert hemozoin. Parasites also express a divergent heme oxygenase (HO)-like protein (PfHO) that lacks key active-site residues and has lost canonical HO activity. The cellular role of this unusual protein that underpins its retention by parasites has been unknown. To unravel PfHO function, we first determined a 2.8 Å-resolution X-ray structure that revealed a highly α-helical fold indicative of distant HO homology. Localization studies unveiled PfHO targeting to the apicoplast organelle, where it is imported and undergoes N-terminal processing but retains most of the electropositive transit peptide. We observed that conditional knockdown of PfHO was lethal to parasites, which died from defective apicoplast biogenesis and impaired isoprenoid-precursor synthesis. Complementation and molecular-interaction studies revealed an essential role for the electropositive N-terminus of PfHO, which selectively associates with the apicoplast genome and enzymes involved in nucleic acid metabolism and gene expression. PfHO knockdown resulted in a specific deficiency in levels of apicoplast-encoded RNA but not DNA. These studies reveal an essential function for PfHO in apicoplast maintenance and suggest thatPlasmodiumrepurposed the conserved HO scaffold from its canonical heme-degrading function in the ancestral chloroplast to fulfill a critical adaptive role in organelle gene expression.

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Section: Figure Supplement 1 Sequence Homologs Of Pfho Based On Blastsupporting

confidence: 89%

Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis

Blackwell,

Jami-Alahmadi,

Nasamu

et al. 2024

Preprint

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“…To distinguish between these possibilities, LAP body structure was examined in dividing parasites by high resolution Airyscan confocal imaging with the modification that GRA3 replaced YFP-SidM-P4M as LAP body marker. In RH-WT parasites, GRA3-positive DGs were distributed throughout the cell during the initiation of mitosis as landmarked by the elongation of the apicoplast (asterisk in Figure 8Ci ; Martins-Duarte et al, 2021). By contrast, parasites expressing YFP-SidM-P4M during the initiation of cell division exhibited a GRA3-positive LAP body ( Figure 8Cii ).…”

Section: Resultsmentioning

confidence: 99%

Phosphatidylinositol-4-phosphate signaling regulates dense granule biogenesis and exocytosis inToxoplasma gondii

Arabiotorre

Formanowicz

Bankaitis

et al. 2023

Preprint

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Phosphoinositide metabolism defines the foundation of a major signaling pathway that is conserved throughout the eukaryotic kingdom. The 4-OH phosphorylated phosphoinositides such as phosphatidylinositol-4-phosphate (PtdIns4P) and phosphatidylinositol-4,5-bisphosphate are particularly important molecules as these execute intrinsically essential activities required for the viability of all eukaryotic cells studied thus far. Using intracellular tachyzoites of the apicomplexan parasite Toxoplasma gondii as model for assessing primordial roles for PtdIns4P signaling, we demonstrate the presence of PtdIns4P pools in Golgi/trans-Golgi (TGN) system and in post-TGN compartments of the parasite. Moreover, we show that deficits in PtdIns4P signaling result in structural perturbation of compartments that house dense granule cargo with accompanying deficits in dense granule exocytosis. Taken together, the data report a direct role for PtdIns4P in dense granule biogenesis and exocytosis. The data further indicate that the biogenic pathway for secretion-competent dense granule formation in T. gondii is more complex than simple budding of fully matured dense granules from the TGN.

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“…In T . gondii , TgTPC is exclusively found in the apicoplast, an endosymbiotic organelle that harbors multiple metabolic pathways required for parasite division [ 252 – 254 ]. Li and colleagues showed that TgTPC is needed for proper formation of apicoplast-ER contact sites and seems to mediate the transference of Ca 2+ between these organelles [ 57 ].…”

Section: Ion Channel Repertoiresmentioning

confidence: 99%

Down the membrane hole: Ion channels in protozoan parasites

Jiménez

Sebastian

2022

PLoS Pathog

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Parasitic diseases caused by protozoans are highly prevalent around the world, disproportionally affecting developing countries, where coinfection with other microorganisms is common. Control and treatment of parasitic infections are constrained by the lack of specific and effective drugs, plus the rapid emergence of resistance. Ion channels are main drug targets for numerous diseases, but their potential against protozoan parasites is still untapped. Ion channels are membrane proteins expressed in all types of cells, allowing for the flow of ions between compartments, and regulating cellular functions such as membrane potential, excitability, volume, signaling, and death. Channels and transporters reside at the interface between parasites and their hosts, controlling nutrient uptake, viability, replication, and infectivity. To understand how ion channels control protozoan parasites fate and to evaluate their suitability for therapeutics, we must deepen our knowledge of their structure, function, and modulation. However, methodological approaches commonly used in mammalian cells have proven difficult to apply in protozoans. This review focuses on ion channels described in protozoan parasites of clinical relevance, mainly apicomplexans and trypanosomatids, highlighting proteins for which molecular and functional evidence has been correlated with their physiological functions.

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Replication and partitioning of the apicoplast genome of Toxoplasma gondii is linked to the cell cycle and requires DNA polymerase and gyrase

Abstract: Graphical abstract

Cited by 13 publications

References 79 publications

Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis

Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis

Phosphatidylinositol-4-phosphate signaling regulates dense granule biogenesis and exocytosis inToxoplasma gondii

Down the membrane hole: Ion channels in protozoan parasites

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