Ubiquitin activation is essential for schizont maturation in Plasmodium falciparum blood-stage development

Green, Judith L.; Encheva, Vesela; Lasonder, Edwin; Prommaban, Adchara; Kunzelmann, Simone; Christodoulou, Evangelos; Grainger, Munira; Truongvan, Ngoc; Bothe, Sebastian; Sharma, Vikram; Song, Wei; Pinzuti, Irene; Uthaipibull, Chairat; Srichairatanakool, Somdet; Birault, Véronique; Langsley, Gordon; Schindelin, Hermann; Stieglitz, Benjamin; Snijders, Ambrosius P.; Holder, Anthony A.

doi:10.1371/journal.ppat.1008640

Cited by 28 publications

(33 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This included genes such as, coatomer subunits (α,β,γ), endoplasmic reticulum chaperone GRP170 and E3-ubiquitin ligase, etc. Interestingly, ubiquitin activation was recently shown to be essential for schizonts maturation 46 . Expression of pH regulation, nucleosome assembly and phosphatidyl inositol biosynthesis related pathways was also higher in SCTS 1, 2 and 3.…”

Section: Resultsmentioning

confidence: 99%

Stochastic Expression of Invasion Genes in Plasmodium falciparum Schizonts

Tripathi

Zhu

Nayak

et al. 2021

Preprint

View full text Add to dashboard Cite

Genetically identical cells are known to exhibit differential phenotypes in the same environmental conditions. These phenotypic variants are linked to transcriptional stochasticity and have been shown to contribute towards adaptive flexibility of a wide range of unicellular organisms. Here, we investigated transcriptional heterogeneity and stochastic gene expression in P. falciparum by performing single cell RNA sequencing on blood stage schizonts. Our data reveals significant transcriptional variations in the schizonts stage with a distinct group of highly variable invasion gene transcripts being identified. Moreover, our data reflected several diversification processes including putative developmental “checkpoint”; transcriptomically distinct parasite sub-populations and transcriptional switches in variable gene families (var, rifin, phist). Most of these features of transcriptional variability were preserved in isogenic parasite cell populations (albeit with a lesser amplitude) suggesting a role of epigenetic factors in cell-to-cell transcriptional variations in human malaria parasites. Lastly, we applied quantitative RT-PCR and RNA-FISH approach and confirmed stochastic expression of merozoites surface proteins encoding msp1, msp3, msp7, rhoptry protein encoding rhopH2 and erythrocyte binding antigen encoding eba181, some of which represent key candidates for invasion blocking vaccines.

show abstract

Section: Resultsmentioning

confidence: 99%

Stochastic Expression of Invasion Genes in Plasmodium falciparum Schizonts

Tripathi

Zhu

Nayak

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…In total, we established 109 putative PfPKA – protein substrate relationships from large scale P. falciparum protein phosphorylation data sets ( Supplementary Table 4 ). Previously, we have described that protein ubiquitylation dramatically increases as schizonts develop into merozoites ( Green et al, 2020 ) and within the list of 109 putative PKA substrates there are 59 ubiquitylated proteins that we had identified previously in the asexual blood stage ubiquitylome ( Green et al, 2020 ). This is a 5.9-fold enrichment compared to the total P. falciparum proteome ( p = 0.00001).…”

Section: Pfpka Therapeutic Target Proteins Identified From P Falciparum Phosphoproteome Datasetsmentioning

confidence: 99%

cAMP-Dependent Signaling Pathways as Potential Targets for Inhibition of Plasmodium falciparum Blood Stages

Lasonder

Singh

et al. 2021

Front. Microbiol.

Self Cite

View full text Add to dashboard Cite

We review the role of signaling pathways in regulation of the key processes of merozoite egress and red blood cell invasion by Plasmodium falciparum and, in particular, the importance of the second messengers, cAMP and Ca2+, and cyclic nucleotide dependent kinases. cAMP-dependent protein kinase (PKA) is comprised of cAMP-binding regulatory, and catalytic subunits. The less well conserved cAMP-binding pockets should make cAMP analogs attractive drug leads, but this approach is compromised by the poor membrane permeability of cyclic nucleotides. We discuss how the conserved nature of ATP-binding pockets makes ATP analogs inherently prone to off-target effects and how ATP analogs and genetic manipulation can be useful research tools to examine this. We suggest that targeting PKA interaction partners as well as substrates, or developing inhibitors based on PKA interaction sites or phosphorylation sites in PKA substrates, may provide viable alternative approaches for the development of anti-malarial drugs. Proximity of PKA to a substrate is necessary for substrate phosphorylation, but the P. falciparum genome encodes few recognizable A-kinase anchor proteins (AKAPs), suggesting the importance of PKA-regulatory subunit myristylation and membrane association in determining substrate preference. We also discuss how Pf14-3-3 assembles a phosphorylation-dependent signaling complex that includes PKA and calcium dependent protein kinase 1 (CDPK1) and how this complex may be critical for merozoite invasion, and a target to block parasite growth. We compare altered phosphorylation levels in intracellular and egressed merozoites to identify potential PKA substrates. Finally, as host PKA may have a critical role in supporting intracellular parasite development, we discuss its role at other stages of the life cycle, as well as in other apicomplexan infections. Throughout our review we propose possible new directions for the therapeutic exploitation of cAMP-PKA-signaling in malaria and other diseases caused by apicomplexan parasites.

show abstract

“…The severity of the TbUBA1b knockdown argues that the sole inhibition of this protein would be sufficient for T. brucei , but such data are not available for T. cruzi and Leishmania . Importantly, a precedent for the targeting of UBA1 in parasites was recently set by the demonstration that TAK243 inhibits the growth and development of Plasmodium ( Green et al, 2020 ). Treatment with TAK-243 was found to result in an absence of viable parasites released from red blood cells.…”

Section: Inhibition Of Ubiquitinationmentioning

confidence: 99%

Ubiquitination and the Proteasome as Drug Targets in Trypanosomatid Diseases

Bijlmakers¹

2021

Front. Chem.

View full text Add to dashboard Cite

The eukaryotic pathogens Trypanosoma brucei, Trypanosoma cruzi and Leishmania are responsible for debilitating diseases that affect millions of people worldwide. The numbers of drugs available to treat these diseases, Human African Trypanosomiasis, Chagas' disease and Leishmaniasis are very limited and existing treatments have substantial shortcomings in delivery method, efficacy and safety. The identification and validation of novel drug targets opens up new opportunities for the discovery of therapeutic drugs with better efficacy and safety profiles. Here, the potential of targeting the ubiquitin-proteasome system in these parasites is reviewed. Ubiquitination is the posttranslational attachment of one or more ubiquitin proteins to substrates, an essential eukaryotic mechanism that regulates a wide variety of cellular processes in many different ways. The best studied of these is the delivery of ubiquitinated substrates for degradation to the proteasome, the major cellular protease. However, ubiquitination can also regulate substrates in proteasome-independent ways, and proteasomes can degrade proteins to some extent in ubiquitin-independent ways. Because of these widespread roles, both ubiquitination and proteasomal degradation are essential for the viability of eukaryotes and the proteins that mediate these processes are therefore attractive drug targets in trypanosomatids. Here, the current understanding of these processes in trypanosomatids is reviewed. Furthermore, significant recent progress in the development of trypanosomatid-selective proteasome inhibitors that cure mouse models of trypanosomatid infections is presented. In addition, the targeting of the key enzyme in ubiquitination, the ubiquitin E1 UBA1, is discussed as an alternative strategy. Important differences between human and trypanosomatid UBA1s in susceptibility to inhibitors predicts that the selective targeting of these enzymes in trypanosomatids may also be feasible. Finally, it is proposed that activating enzymes of the ubiquitin-like proteins SUMO and NEDD8 may represent drug targets in these trypanosomatids as well.

show abstract

Ubiquitin activation is essential for schizont maturation in Plasmodium falciparum blood-stage development

Cited by 28 publications

References 76 publications

Stochastic Expression of Invasion Genes in Plasmodium falciparum Schizonts

Stochastic Expression of Invasion Genes in Plasmodium falciparum Schizonts

cAMP-Dependent Signaling Pathways as Potential Targets for Inhibition of Plasmodium falciparum Blood Stages

Ubiquitination and the Proteasome as Drug Targets in Trypanosomatid Diseases

Contact Info

Product

Resources

About