scholarly journals Protein Prenylation and Hsp40 in Thermotolerance of Plasmodium falciparum Malaria Parasites

mBio ◽  
2021 ◽  
Author(s):  
Emily S. Mathews ◽  
Andrew J. Jezewski ◽  
Audrey R. Odom John
Keyword(s):  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Malaria Parasite ◽  
Plasmodium Falciparum Malaria ◽  
Complex Life Cycle ◽  
Large Temperature ◽  
Protein Prenylation ◽  
Content Type

During its complex life cycle, the malaria parasite survives dramatic environmental stresses, including large temperature shifts. Protein prenylation is required during asexual replication of Plasmodium falciparum , and the canonical heat shock protein 40 protein (HSP40; PF3D7_1437900) is posttranslationally modified with a 15-carbon farnesyl isoprenyl group.

scholarly journals Protein prenylation and Hsp40 in thermotolerance of Plasmodium falciparum malaria parasites

2019 ◽  
Author(s):  
Emily S. Mathews ◽  
Andrew J. Jezewski ◽  
Audrey R. Odom John
Keyword(s):  
Plasmodium Falciparum ◽  
Heat Shock ◽  
Malaria Parasite ◽  
Plasmodium Falciparum Malaria ◽  
Complex Life Cycle ◽  
Protein Prenylation ◽  
Membrane Attachment ◽  
Client Proteins ◽  
Essential Function ◽  
And Function

AbstractDuring its complex life cycle, the malaria parasite survives dramatic changes in environmental temperature. Protein prenylation is required during asexual replication of Plasmodium falciparum, and heat shock protein 40 (HSP40; PF3D7_1437900) is post-translationally modified with a 15-carbon farnesyl isoprenyl group. In other organisms, farnesylation of Hsp40 orthologs controls its localization and function, including temperature stress survival. In this work, we find that plastidial isopentenyl pyrophosphate (IPP) synthesis and protein farnesylation are required for malaria parasite survival after cold and heat shock. Furthermore, loss of HSP40 farnesylation alters its membrane attachment and interaction with proteins involved in crucial biological processes, such as glycolysis and cytoskeletal organization. Together, this work reveals that farnesylation of HSP40 in P. falciparum is a novel essential function of plastidial isoprenoid biosynthesis. We propose a model by which farnesyl-HSP40 promotes parasite thermotolerance and facilitates vesicular trafficking through its interaction with client proteins.

scholarly journals A Novel Tool for the Generation of Conditional Knockouts To Study Gene Function across the Plasmodium falciparum Life Cycle

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Marta Tibúrcio ◽  
Annie S. P. Yang ◽  
Kazuhide Yahata ◽  
Pablo Suárez-Cortés ◽  
Hugo Belda ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Genetic Modification ◽  
Gene Deletion ◽  
Genetically Modify ◽  
Complex Life Cycle ◽  
Mosquito Vector ◽  
Parasite Line ◽  
Content Type ◽  
First Time

ABSTRACT Plasmodium falciparum has a complex life cycle that involves interaction with multiple tissues inside the human and mosquito hosts. Identification of essential genes at all different stages of the P. falciparum life cycle is urgently required for clinical development of tools for malaria control and eradication. However, the study of P. falciparum is limited by the inability to genetically modify the parasite throughout its life cycle with the currently available genetic tools. Here, we describe the detailed characterization of a new marker-free P. falciparum parasite line that expresses rapamycin-inducible Cre recombinase across the full life cycle. Using this parasite line, we were able to conditionally delete the essential invasion ligand AMA1 in three different developmental stages for the first time. We further confirm efficient gene deletion by targeting the nonessential kinase FIKK7.1. IMPORTANCE One of the major limitations in studying P. falciparum is that so far only asexual stages are amenable to rapid conditional genetic modification. The most promising drug targets and vaccine candidates, however, have been refractory to genetic modification because they are essential during the blood stage or for transmission in the mosquito vector. This leaves a major gap in our understanding of parasite proteins in most life cycle stages and hinders genetic validation of drug and vaccine targets. Here, we describe a method that supports conditional gene deletion across the P. falciparum life cycle for the first time. We demonstrate its potential by deleting essential and nonessential genes at different parasite stages, which opens up completely new avenues for the study of malaria and drug development. It may also allow the realization of novel vaccination strategies using attenuated parasites.

scholarly journals Mitosis in the Human Malaria Parasite Plasmodium falciparum

2011 ◽  
Vol 10 (4) ◽  
pp. 474-482 ◽  
Author(s):  
Noel Gerald ◽  
Babita Mahajan ◽  
Sanjai Kumar
Keyword(s):  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Complex Life Cycle ◽  
Anopheline Mosquito ◽  
Essential Requirement ◽  
Human Malaria Parasite ◽  
Content Type ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum ◽  
Key Events

ABSTRACT Malaria is caused by intraerythrocytic protozoan parasites belonging to Plasmodium spp. (phylum Apicomplexa ) that produce significant morbidity and mortality, mostly in developing countries. Plasmodium parasites have a complex life cycle that includes multiple stages in anopheline mosquito vectors and vertebrate hosts. During the life cycle, the parasites undergo several cycles of extreme population growth within a brief span, and this is critical for their continued transmission and a contributing factor for their pathogenesis in the host. As with other eukaryotes, successful mitosis is an essential requirement for Plasmodium reproduction; however, some aspects of Plasmodium mitosis are quite distinct and not fully understood. In this review, we will discuss the current understanding of the architecture and key events of mitosis in Plasmodium falciparum and related parasites and compare them with the traditional mitotic events described for other eukaryotes.

scholarly journals Malaria Parasite Stress Tolerance Is Regulated by DNMT2-Mediated tRNA Cytosine Methylation

mBio ◽  
2021 ◽  
Author(s):  
Elie Hammam ◽  
Ameya Sinha ◽  
Sebastian Baumgarten ◽  
Flore Nardella ◽  
Jiaqi Liang ◽  
...  
Keyword(s):  
Life Cycle ◽  
Malaria Parasite ◽  
Cytosine Methylation ◽  
Parasite Species ◽  
Environmental Stressors ◽  
Complex Life Cycle ◽  
Content Type ◽  
Mortality And Morbidity ◽  
Disease Mortality ◽  
New Strategies

P. falciparum is the most virulent malaria parasite species, accounting for the majority of the disease mortality and morbidity. Understanding how this pathogen is able to adapt to different cellular and environmental stressors during its complex life cycle is crucial in order to develop new strategies to tackle the disease.

scholarly journals Predicting gene expression in the human malaria parasite Plasmodium falciparum

2018 ◽  
Author(s):  
David F. Read ◽  
Yang Y. Lu ◽  
Kate Cook ◽  
Karine Le Roch ◽  
William Stafford Noble
Keyword(s):  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Histone Modifications ◽  
Malaria Parasite ◽  
Nucleosome Occupancy ◽  
Gc Content ◽  
Complex Life Cycle ◽  
Data Sets ◽  
3D Genome ◽  
Parasite Plasmodium Falciparum

AbstractEmpirical evidence suggests that the malaria parasite Plasmodium falciparum employs a broad range of mechanisms to regulate gene transcription throughout the organism’s complex life cycle. To better understand this regulatory machinery, we assembled a rich collection of genomic and epigenomic data sets, including information about transcription factor (TF) binding motifs, patterns of covalent histone modifications, nucleosome occupancy, GC content, and global 3D genome architecture. We used these data to train machine learning models to discriminate between high-expression and low-expression genes, focusing on three distinct stages of the red blood cell phase of the Plasmodium life cycle. Our results highlight the importance of histone modifications and 3D chromatin architecture and suggest a relatively small role for TF binding in Plasmodium transcriptional regulation.

scholarly journals Plasmodium falciparum Cyclic GMP-Dependent Protein Kinase Interacts with a Subunit of the Parasite Proteasome

2018 ◽  
Vol 87 (1) ◽  
Author(s):  
K. Govindasamy ◽  
R. Khan ◽  
M. Snyder ◽  
H. J. Lou ◽  
P. Du ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Protein Kinase ◽  
Cyclic Gmp ◽  
Phosphorylation Site ◽  
Complex Life Cycle ◽  
Mosquito Vector ◽  
Dependent Protein Kinase ◽  
Content Type ◽  
Dependent Protein

ABSTRACT Malaria is caused by the protozoan parasite Plasmodium, which undergoes a complex life cycle in a human host and a mosquito vector. The parasite’s cyclic GMP (cGMP)-dependent protein kinase (PKG) is essential at multiple steps of the life cycle. Phosphoproteomic studies in Plasmodium falciparum erythrocytic stages and Plasmodium berghei ookinetes have identified proteolysis as a major biological pathway dependent on PKG activity. To further understand PKG’s mechanism of action, we screened a yeast two-hybrid library for P. falciparum proteins that interact with P. falciparum PKG (PfPKG) and tested peptide libraries to identify its phosphorylation site preferences. Our data suggest that PfPKG has a distinct phosphorylation site and that PfPKG directly phosphorylates parasite RPT1, one of six AAA+ ATPases present in the 19S regulatory particle of the proteasome. PfPKG and RPT1 interact in vitro, and the interacting fragment of RPT1 carries a PfPKG consensus phosphorylation site; a peptide carrying this consensus site competes with the RPT1 fragment for binding to PfPKG and is efficiently phosphorylated by PfPKG. These data suggest that PfPKG’s phosphorylation of RPT1 could contribute to its regulation of parasite proteolysis. We demonstrate that proteolysis plays an important role in a biological process known to require Plasmodium PKG: invasion by sporozoites of hepatocytes. A small-molecule inhibitor of proteasomal activity blocks sporozoite invasion in an additive manner when combined with a Plasmodium PKG-specific inhibitor. Mining the previously described parasite PKG-dependent phosphoproteomes using the consensus phosphorylation motif identified additional proteins that are likely to be direct substrates of the enzyme.

scholarly journals Dispensable Role of Mitochondrial Fission Protein 1 (Fis1) in the Erythrocytic Development of Plasmodium falciparum

mSphere ◽  
2020 ◽  
Vol 5 (5) ◽  
Author(s):  
Mulaka Maruthi ◽  
Liqin Ling ◽  
Jing Zhou ◽  
Hangjun Ke
Keyword(s):  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Outer Membrane ◽  
Malaria Parasite ◽  
Mitochondrial Fission ◽  
Adaptor Proteins ◽  
Mitochondrial Outer Membrane ◽  
Content Type ◽  
Single Mitochondrion

ABSTRACT Malaria remains a huge global health burden, and control of this disease has run into a severe bottleneck. To defeat malaria and reach the goal of eradication, a deep understanding of the parasite biology is urgently needed. The mitochondrion of the malaria parasite is essential throughout the parasite’s life cycle and has been validated as a clinical drug target. In the asexual development of Plasmodium spp., the single mitochondrion grows from a small tubular structure to a complex branched network. This branched mitochondrion is divided at the end of schizogony when 8 to 32 daughter cells are produced, distributing one mitochondrion to each forming merozoite. In mosquito and liver stages, the giant mitochondrial network is split into thousands of pieces and daughter mitochondria are segregated into individual progeny. Despite the significance of mitochondrial fission in Plasmodium, the underlying mechanism is largely unknown. Studies of mitochondrial fission in model eukaryotes have revealed that several mitochondrial fission adaptor proteins are involved in recruiting dynamin GTPases to physically split mitochondrial membranes. Apicomplexan parasites, however, share no identifiable homologs of mitochondrial fission adaptor proteins with yeast or humans, except for Fis1. Here, we investigated the localization and essentiality of the Fis1 homolog in Plasmodium falciparum, PfFis1 (PF3D7_1325600), during the asexual life cycle. We found that PfFis1 requires an intact C terminus for mitochondrial localization but is not essential for parasite development or mitochondrial fission. The dispensable role of PfFis1 indicates that Plasmodium contains additional fission adaptor proteins on the mitochondrial outer membrane that could be essential for mitochondrial fission. IMPORTANCE Malaria is responsible for over 230 million clinical cases and ∼half a million deaths each year. The single mitochondrion of the malaria parasite functions as a metabolic hub throughout the parasite’s developmental cycle (DC) and also as a source of ATP in certain stages. To pass on its essential functions, the parasite’s mitochondrion needs to be properly divided and segregated into all progeny during cell division via a process termed mitochondrial fission. Due to the divergent nature of Plasmodium spp., the molecular players involved in mitochondrial fission and their mechanisms of action remain largely unknown. Here, we found that the only identifiable mitochondrial fission adaptor protein that is evolutionarily conserved in the Apicomplexan phylum, Fis1, it not essential in P. falciparum asexual stages. Our data suggest that malaria parasites use redundant fission adaptor proteins on the mitochondrial outer membrane to mediate the fission process.

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