Identification of a novel post-translational modification in<i>Plasmodium falciparum</i>: protein sumoylation in different cellular compartments

Issar, Neha; Roux, Emeric; Mattei, Denise; Scherf, Artur

doi:10.1111/j.1462-5822.2008.01183.x

Cited by 60 publications

(74 citation statements)

References 41 publications

(50 reference statements)

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“…The proposed function of heterologous SUMO/UB chains is to target sumoylated proteins to the proteasome for degradation. Various SUMO targets were previously reported and indicated an important role of sumoylation in the parasite's biology (57). Among them, Issar et al (57) identified several transcription and chromatin regulators, including the histone protein H4 (PF11_0061) that we also identified in our data set.…”

Section: Discussionsupporting

confidence: 52%

“…Various SUMO targets were previously reported and indicated an important role of sumoylation in the parasite's biology (57). Among them, Issar et al (57) identified several transcription and chromatin regulators, including the histone protein H4 (PF11_0061) that we also identified in our data set. Our results further suggest that the histone variant H2A.Z (and possibly H2A, H2B, and H3) is also a target for ubiquitylation.…”

Section: Discussionsupporting

confidence: 52%

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Unraveling the Ubiquitome of the Human Malaria Parasite

Ponts

Saraf

Chung

et al. 2011

Journal of Biological Chemistry

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Malaria is one of the deadliest infectious diseases worldwide. The most severe form is caused by the eukaryotic protozoan parasite Plasmodium falciparum. Recent studies have highlighted the importance of post-translational regulations for the parasite's progression throughout its life cycle, protein ubiquitylation being certainly one of the most abundant. The specificity of its components and the wide range of biological processes in which it is involved make the ubiquitylation pathway a promising source of suitable targets for anti-malarial drug development. Here, we combined immunofluorescent microscopy, biochemical assays, in silico prediction, and mass spectrometry analysis using the multidimensional protein identification technology, or MudPIT, to describe the P. falciparum ubiquitome. We found that ubiquitin conjugates are detected at every morphological stage of the parasite erythrocytic cycle. Furthermore, we detected that more than half of the parasite's proteome represents possible targets for ubiquitylation, especially proteins found to be present at the most replicative stage of the asexual cycle, the trophozoite stage. A large proportion of ubiquitin conjugates were also detected at the schizont stage, consistent with a cell activity slowdown to prepare for merozoite differentiation and invasion. Finally, for the first time in the human malaria parasite, our results strongly indicate the presence of heterologous mixed conjugations, SUMO/UB. This discovery suggests that sumoylated proteins may be regulated by ubiquitylation in P. falciparum. Altogether, our results present the first stepping stone toward a better understanding of ubiquitylation and its role(s) in the biology of the human malaria parasite.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionsupporting

confidence: 52%

Unraveling the Ubiquitome of the Human Malaria Parasite

Ponts

Saraf

Chung

et al. 2011

Journal of Biological Chemistry

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“…There is no evidence of PfH3S10 phosphorylation yet, as is commonly observed in model eukaryotes. For other histone PTMs, H4 is found sumoylated, while H2B is ubiquitinated at K112 (74,147). Taken together, the sheer number of conserved and novel PTMs on canonical and variant histones in P. falciparum demonstrates the potential complexity of the "histone code" in this parasite.…”

Section: Malaria Parasite Histones and "Histone Code"mentioning

confidence: 88%

“…The malaria parasite genomes contain a number of protein homologues of E1, E2, and E3 and a number of proteases that might be involved in removing the Ubl modifications (118,120). In an effort to identify the proteome of PfSUMO modified proteins, Issar et al (74) identified sumoylated histone H4 from P. falciparum. Interestingly, PfSir2A is also a target for sumoylation, suggesting cross talk between these two epigenetic pathways.…”

Section: Chromatin Modifications: Deposition Recognition and Functionsmentioning

confidence: 99%

Chromatin-Mediated Epigenetic Regulation in the Malaria Parasite Plasmodium falciparum

2010

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Malaria is a major public health problem in many developing countries, with the malignant tertian parasite Plasmodium falciparum causing the most malaria-associated mortality. Extensive research, especially with the advancement of genomics and transfection tools, has highlighted the fundamental importance of chromatinmediated gene regulation in the developmental program of this early-branching eukaryote. The Plasmodium parasite genomes reveal the existence of both canonical and variant histones that make up the nucleosomes, as well as a full collection of conserved enzymes for chromatin remodeling and histone posttranslational modifications (PTMs). Recent studies have identified a wide array of both conserved and novel histone PTMs in P. falciparum, indicating the presence of a complex and divergent "histone code." Genome-wide analysis has begun to decipher the nucleosome landscape and histone modifications associated with the dynamic organization of chromatin structures during the parasite's life cycle. Focused studies on malaria-specific phenomena such as antigenic variation and red cell invasion pathways shed further light on the involvement of epigenetic mechanisms in these processes. Here we review our current understanding of chromatin-mediated gene regulation in malaria parasites, with specific reference to exemplar studies on antigenic variation and host cell invasion.Malaria continues to be a major cause of mortality and morbidity in tropical countries, bringing a death toll of ϳ1 million each year. Four human parasites (Plasmodium falciparum, P. vivax, P. malariae, and P. ovale) and a monkey parasite (P. knowlesi) have been found to infect humans naturally. P. falciparum causes the malignant form of malaria and is responsible for most malaria-associated human deaths. Intensified research in the past decade has greatly improved our understanding of the parasites and the disease they cause, especially with the sequencing of multiple parasite genomes. A striking finding from global microarray analyses of parasite gene expression is the tightly regulated transcription program during the parasite's life cycle, with genes expressed in a "just-in-time" manner (12, 93). Bioinformatic analysis has recognized a general conservation of the basal transcription machinery (15), but the scarcity of recognizable specific transcription factors in the parasite genome has led to speculation about the existence of a divergent transcription mechanism used by the malaria parasites (2, 25). However, this speculation may be inaccurate, as recent studies revealed the presence of the AP2 family of transcription factors (4, 35), which have undergone lineagespecific expansion in apicomplexan parasites (75). Nevertheless, the full complement of chromatin-modifying proteins encoded in apicomplexan parasite genomes underlines the significance of epigenetic mechanisms in transcription regulation (2,66,75,140). While epigenetic mechanisms are being intensively studied in model eukaryotes, only recently have they been explored in the m...

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“…In brief, histone tails can be acetylated, methylated, and sumoylated as in higher eukaryotes (54,55,77), and the parasite accordingly possesses histone acetylases, deacetylases, methylases, and demethylases, several of which have been characterized (35,37,75).…”

Section: What Do We Know About the Epigenetic Machinery In Plasmodium?mentioning

confidence: 99%

Epigenetics in Plasmodium: What Do We Really Know?

Merrick

Duraisingh

2010

Eukaryot Cell

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In the burgeoning field of Plasmodium gene expression, there are-to borrow some famous words from a former U.S. Secretary of Defense-"known knowns, known unknowns, and unknown unknowns." This is in itself an important achievement, since it is only in the past decade that facts have begun to move from the third category into the first. Nevertheless, much remains in the middle ground of known or suspected "unknowns." It is clear that the malaria parasite controls vital virulence processes such as host cell invasion and cytoadherence at least partly via epigenetic mechanisms, so a proper understanding of epigenetic transcriptional control in this organism should have great clinical relevance. Plasmodium, however, is an obligate intracellular parasite: it operates not in a vacuum but rather in the complicated context of its metazoan hosts. Therefore, as valuable data about the parasite's basic epigenetic machinery begin to emerge, it becomes increasingly important to relate in vitro studies to the situation in vivo. This review will focus upon the challenge of understanding Plasmodium epigenetics in an integrated manner, in the human and insect hosts as well as the petri dish. WHY DOES EPIGENETICS MATTER IN PLASMODIUM?The malaria parasite has a complicated life cycle involving several functionally distinct forms living in two very different host species. It must be able to perform rapid transitions between morphological states and also long-term antigenic variation to sustain chronic infections in human hosts. To achieve all this, the parasite employs various types of regulation, including transcriptional and posttranscriptional regulation of gene expression, translational repression, and posttranslational protein modification. While several of these regulatory modes are suited to respond rapidly to host conditions during an acute infection or a life cycle transition, only the epigenetic control of gene expression can then maintain that "imprinted" pattern in later generations. (The term "epigenetic" will be used here to refer to the heritable marking of genetic material without alterations in the actual genetic code.) Epigenetic mechanisms of transcriptional control are thus likely to act in at least three major areas of Plasmodium biology.The first area is the cascade of changing gene expression which occurs during asexual replication in the human bloodstream. This is the most studied stage of the life cycle and the one which causes all the clinical symptoms of malaria. Plasmodium falciparum, the main Plasmodium species responsible for human mortality, has an unusual, formulaic mode of gene expression during its 48-h developmental process inside the erythrocyte, implying tight and integrated genome-wide regulation of transcription (13,62,65). It was initially thought that the Plasmodium genus had a striking paucity of classical transcription factors because few could be found in the sequenced genome of P. falciparum (49), and epigenetics was postulated as an alternative primary mode of transcriptional regulation. ...

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Identification of a novel post-translational modification inPlasmodium falciparum: protein sumoylation in different cellular compartments

Cited by 60 publications

References 41 publications

Unraveling the Ubiquitome of the Human Malaria Parasite

Unraveling the Ubiquitome of the Human Malaria Parasite

Chromatin-Mediated Epigenetic Regulation in the Malaria Parasite Plasmodium falciparum

Epigenetics in Plasmodium: What Do We Really Know?

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