Structure and Content of the Entamoeba histolytica Genome

Clark, C. Graham; Uc, Alsmark; Tazreiter, Margit; Saito‐Nakano, Yumiko; Ali, Sajid; Marion, Sabrina; Weber, Christian; Mukherjee, Chandrama; Bruchhaus, Iris; Tannich, Egbert; Leippe, Matthias; Sicheritz-Pontén, Thomas; Foster, Peter G.; Samuelson, John; Cj, Noël; Hirt, Robert P.; Embley, T. Martin; Ca, Gilchrist; Bj, Mann; Singh, Upinder; Jp, Ackers; Bhattacharya, Sudha; Bhattacharya, Alok; Lohia, Anuradha; Guillén, Nancy; Duchêne, Michael; Nozaki, Tomoyoshi; Hall, Neil

doi:10.1016/s0065-308x(07)65002-7

Cited by 172 publications

(171 citation statements)

References 504 publications

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“…This event could be key for adaptation to a parasitic lifestyle in the host. This assumption is supported by the fact that Entamoeba, which is known to have no pathways for de novo cholesterol synthesis (23,24), inhabits a niche in vertebrate intestines that is rich in cholesterol (25,26), an essential precursor for synthesizing CS (11,12). Hence, we propose a scenario for the evolution of anaerobic amoeba in line with MRO functions (Fig.…”

Section: Discussionmentioning

confidence: 70%

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Entamoeba mitosomes play an important role in encystation by association with cholesteryl sulfate synthesis

Mi-ichi

Miyamoto

Takao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

114

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Hydrogenosomes and mitosomes are mitochondrion-related organelles (MROs) that have highly reduced and divergent functions in anaerobic/microaerophilic eukaryotes. Entamoeba histolytica, a microaerophilic, parasitic amoebozoan species, which causes intestinal and extraintestinal amoebiasis in humans, possesses mitosomes, the existence and biological functions of which have been a longstanding enigma in the evolution of mitochondria. We previously demonstrated that sulfate activation, which is not generally compartmentalized to mitochondria, is a major function of E. histolytica mitosomes. However, because the final metabolites of sulfate activation remain unknown, the overall scheme of this metabolism and the role of mitosomes in Entamoeba have not been elucidated. In this study we purified and identified cholesteryl sulfate (CS) as a final metabolite of sulfate activation. We then identified the gene encoding the cholesteryl sulfotransferase responsible for synthesizing CS. Addition of CS to culture media increased the number of cysts, the dormant form that differentiates from proliferative trophozoites. Conversely, chlorate, a selective inhibitor of the first enzyme in the sulfate-activation pathway, inhibited cyst formation in a dose-dependent manner. These results indicate that CS plays an important role in differentiation, an essential process for the transmission of Entamoeba between hosts. Furthermore, we show that Mastigamoeba balamuthi, an anaerobic, free-living amoebozoan species, which is a close relative of E. histolytica, also has the sulfate-activation pathway in MROs but does not possess the capacity for CS production. Hence, we propose that a unique function of MROs in Entamoeba contributes to its adaptation to its parasitic life cycle. mitochondrion-related organelles | protist | sulfolipids | differentiation M itochondrion-related organelles (MROs) are derived from canonical mitochondria and are found in a wide range of anaerobic/microaerophilic eukaryotes (1, 2). During the course of evolution MROs have undergone secondary loss of mitochondrial functions; this loss has occurred independently multiple times, resulting in the broad phylogenetic distribution of organisms possessing MROs (2). Furthermore, MROs occasionally acquire novel functions from other organisms by lateral gene transfer (LGT) (1, 3). Hence, MROs are not simply remnants of mitochondria but rather are organelles that display a variety of unique features (1-5).Unique features have been demonstrated in different types of MRO (2-4). Some anaerobic lineages of eukaryotes possess MROs (hydrogenosomes or hydrogen-producing mitochondria) that have remodeled their mitochondria drastically to couple ATP generation with hydrogen production (2-4). Mitosomes, another type of MRO maintained in some organisms that inhabit anaerobic/microaerophilic environments, do not produce ATP or hydrogen and have lost typical mitochondrial functions, such as the tricarboxylic acid (TCA) cycle, electron transport, oxidative phosphorylation, and β-oxidation...

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Section: Discussionmentioning

confidence: 70%

“…Entamoeba can synthesize CS via SULT6, using PAPS and cholesterol as substrates. PAPS is synthesized by the Entamoeba mitosomal sulfate-activation pathway, whereas there is no de novo synthetic pathway for cholesterol in Entamoeba (23,24). Thus, Entamoeba rely on the external milieu as the source of cholesterol.…”

Section: Discussionmentioning

confidence: 99%

Entamoeba mitosomes play an important role in encystation by association with cholesteryl sulfate synthesis

Mi-ichi

Miyamoto

Takao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

114

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“…Thus, we concluded that the YxxL motif is not likely involved in the recruitment of this family of receptors/carriers in E. histolytica. This is surprising, as the major components of the AP complex and clathrins are conserved in E. histolytica (35,36), and the motif is known to bind to the -subunit of the complex.…”

Section: Discussionmentioning

confidence: 99%

Cysteine Protease-Binding Protein Family 6 Mediates the Trafficking of Amylases to Phagosomes in the Enteric Protozoan Entamoeba histolytica

2013

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cPhagocytosis plays a pivotal role in nutrient acquisition and evasion from the host defense systems in Entamoeba histolytica, the intestinal protozoan parasite that causes amoebiasis. We previously reported that E. histolytica possesses a unique class of a hydrolase receptor family, designated the cysteine protease-binding protein family (CPBF), that is involved in trafficking of hydrolases to lysosomes and phagosomes, and we have also reported that CPBF1 and CPBF8 bind to cysteine proteases or ␤-hexosaminidase ␣-subunit and lysozymes, respectively. In this study, we showed by immunoprecipitation that CPBF6, one of the most highly expressed CPBF proteins, specifically binds to ␣-amylase and ␥-amylase. We also found that CPBF6 is localized in lysosomes, based on immunofluorescence imaging. Immunoblot and proteome analyses of the isolated phagosomes showed that CPBF6 mediates transport of amylases to phagosomes. We also demonstrated that the carboxyl-terminal cytosolic region of CPBF6 is engaged in the regulation of the trafficking of CPBF6 to phagosomes. Our proteome analysis of phagosomes also revealed new potential phagosomal proteins.

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“…Cysteine proteinases are well described virulence factors of the human enteric pathogen, E. histolytica (5,11,14,17). Recent reports identified differential expression of the cysteine proteinase genes in cysts and trophozoites obtained from in Arrow, prepro-EhCP4 (ϳ34 kDa); hollow arrowheads, pro-EhCP4 (ϳ32 kDa); star, mature EhCP4 (ϳ26 kDa); black arrowhead, degraded EhCP4.…”

Section: Discussionmentioning

confidence: 99%

A Novel Entamoeba histolytica Cysteine Proteinase, EhCP4, Is Key for Invasive Amebiasis and a Therapeutic Target

Nora

Schneider

et al. 2010

Journal of Biological Chemistry

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Entamoeba histolytica cysteine proteinases (EhCPs) play a key role in disrupting the colonic epithelial barrier and the innate host immune response during invasion of E. histolytica, the protozoan cause of human amebiasis. EhCPs are encoded by 50 genes, of which ehcp4 (ehcp-a4) is the most up-regulated during invasion and colonization in a mouse cecal model of amebiasis. Up-regulation of ehcp4 in vivo correlated with our finding that co-culture of E. histolytica trophozoites with mucin-producing T84 cells increased ehcp4 expression up to 6-fold. We have expressed recombinant EhCP4, which was autocatalytically activated at acidic pH but had highest proteolytic activity at neutral pH. In contrast to the other amebic cysteine proteinases characterized so far, which have a preference for arginine in the P2 position, EhCP4 displayed a unique preference for valine and isoleucine at P2. This preference was confirmed by homology modeling, which revealed a shallow, hydrophobic S2 pocket. Endogenous EhCP4 localized to cytoplasmic vesicles, the nuclear region, and perinuclear endoplasmic reticulum (ER). Following co-culture with colonic cells, EhCP4 appeared in acidic vesicles and was released extracellularly. A specific vinyl sulfone inhibitor, WRR605, synthesized based on the substrate specificity of EhCP4, inhibited the recombinant enzyme in vitro and significantly reduced parasite burden and inflammation in the mouse cecal model. The unique expression pattern, localization, and biochemical properties of EhCP4 could be exploited as a potential target for drug design.

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Structure and Content of the Entamoeba histolytica Genome

Cited by 172 publications

References 504 publications

Entamoeba mitosomes play an important role in encystation by association with cholesteryl sulfate synthesis

Entamoeba mitosomes play an important role in encystation by association with cholesteryl sulfate synthesis

Cysteine Protease-Binding Protein Family 6 Mediates the Trafficking of Amylases to Phagosomes in the Enteric Protozoan Entamoeba histolytica

A Novel Entamoeba histolytica Cysteine Proteinase, EhCP4, Is Key for Invasive Amebiasis and a Therapeutic Target

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