Apicomplexan rhomboids have a potential role in microneme protein cleavage during host cell invasion

Dowse, Timothy J.; Pascall, John C.; Brown, Kenneth D.; Soldati, Dominique

doi:10.1016/j.ijpara.2005.04.001

Cited by 112 publications

(138 citation statements)

References 46 publications

(63 reference statements)

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“…Such a cleavage event is supported by the presence of a putative rhomboid cleavage site in the transmembrane domain of MTRAP (Fig. 4C) and the essential nature that this cleavage has for other TRAP homologues (42,43,45). A ϳ30-kDa band detectable in 3D7-MTRAP-GFP parasite material (Fig.…”

Section: Mtrap Is Released Onto the Merozoite Surface And Processed Dmentioning

confidence: 90%

“…4C). In addition to features of the cytoplasmic tail, intramembrane cleavage of TRAP/ MIC2 also appears to be essential for TRAP function (41), with cleavage thought to occur via an intramembrane rhomboid protease (42)(43)(44)(45). Alignment of the C-terminal regions of the eight TSR-containing genes (with TgMIC2), shows that only four of the eight have a putative rhomboid cleavage site (Fig.…”

Section: Motor Complex Proteins Pfgap45 and Pfgap50 Are Expressed Inmentioning

confidence: 99%

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A Conserved Molecular Motor Drives Cell Invasion and Gliding Motility across Malaria Life Cycle Stages and Other Apicomplexan Parasites

Baum

Richard

Healer

et al. 2006

Journal of Biological Chemistry

334

390

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Apicomplexan parasites constitute one of the most significant groups of pathogens infecting humans and animals. The liver stage sporozoites of Plasmodium spp. and tachyzoites of Toxoplasma gondii, the causative agents of malaria and toxoplasmosis, respectively, use a unique mode of locomotion termed gliding motility to invade host cells and cross cell substrates. This amoeboid-like movement uses a parasite adhesin from the thrombospondin-related anonymous protein (TRAP) family and a set of proteins linking the extracellular adhesin, via an actin-myosin motor, to the inner membrane complex. The Plasmodium blood stage merozoite, however, does not exhibit gliding motility. Here we show that homologues of the key proteins that make up the motor complex, including the recently identified glideosome-associated proteins 45 and 50 (GAP40 and GAP50), are present in P. falciparum merozoites and appear to function in erythrocyte invasion. Furthermore, we identify a merozoite TRAP homologue, termed MTRAP, a micronemal protein that shares key features with TRAP, including a thrombospondin repeat domain, a putative rhomboid-protease cleavage site, and a cytoplasmic tail that, in vitro, binds the actinbinding protein aldolase. Analysis of other parasite genomes shows that the components of this motor complex are conserved across diverse Apicomplexan genera. Conservation of the motor complex suggests that a common molecular mechanism underlies all Apicomplexan motility, which, given its unique properties, highlights a number of novel targets for drug intervention to treat major diseases of humans and livestock.Parasites from the phylum Apicomplexa represent some of the most significant human and agricultural pathogens. Their ranks include Theileria parva and Theileria annulata, parasites that give rise to lymphoproliferative diseases of cattle, the opportunistic pathogens Toxoplasma gondii and Cryptosporidium parvum that can cause life-threatening, prolonged infection in immunocompromised patients, and the most lethal of the group, the genus Plasmodium, in particular Plasmodium falciparum, the cause of millions of human deaths and as many as 500 million infections annually (1).Apicomplexa are a monophyletic group of obligate intracellular parasites that invade a wide range of host cells but lack the classical means of motility such as a flagellum or cilia. Instead, they move by a unique form of actin-based locomotion called gliding motility (for recent reviews, see Refs. 2-4). Efficient motility and invasion requires the release of proteins from secretory organelles located at the apical prominence, the defining structure of the phylum. These organelles, the micronemes, rhoptries, and dense granules contain many of the key proteins needed for directional attachment, cell invasion, and establishment of the parasitophorous vacuole (PV) 5 within the host cell (5). Much of our understanding of gliding motility comes from studies with the liver stage parasite from Plasmodium spp., the sporozoite, or the morphologically similar tac...

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Section: Mtrap Is Released Onto the Merozoite Surface And Processed Dmentioning

confidence: 90%

Section: Motor Complex Proteins Pfgap45 and Pfgap50 Are Expressed Inmentioning

confidence: 99%

A Conserved Molecular Motor Drives Cell Invasion and Gliding Motility across Malaria Life Cycle Stages and Other Apicomplexan Parasites

Baum

Richard

Healer

et al. 2006

Journal of Biological Chemistry

334

390

View full text Add to dashboard Cite

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“…The MPP1 activity is essential at least for TgMIC2 since overexpression of a cleavage site mutant of TgMIC2 blocked invasion [44]. The first experimental evidence that a rhomboid protease was responsible for the MPP1 activity came for the analysis of TgMICs in cell based cleavage assays [50,52,53]. Subsequently, Plasmodium falciparum PfEBA-175 [48], PfAMA1 [45], PfRh1, PfRh4 [49] and PfTRAP (P. Sinnis, personal communication) were reported to be cleaved by a rhomboid-like activity in vivo, whereas PfCTRP, PfM-TRAP and PfMAEBL were shown to be rhomboid substrates in vitro [50].…”

Section: Apicomplexansmentioning

confidence: 99%

“…TgROM1 is a micronemal protein, which is catalytically active in vitro against Spitz, but its physiological substrate(s) are unknown [52,53]. In P. falciparum, ROM1 has been localized to either a new secretory organelle called mononeme [54] or to the micronemes [48].…”

Section: Apicomplexansmentioning

confidence: 99%

New insights into parasite rhomboid proteases

Santos

Graindorge

Soldati‐Favre

2012

Molecular and Biochemical Parasitology

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a b s t r a c tThe rhomboid-like proteins constitute a large family of intramembrane serine proteases that are present in all branches of life. First studied in Drosophila, these enzymes catalyse the release of the active forms of proteins from the membrane and hence trigger signalling events. In protozoan parasites, a limited number of rhomboid-like proteases have been investigated and some of them are associated to pathogenesis. In Apicomplexans, rhomboid-like protease activity is involved in shedding adhesins from the surface of the zoites during motility and host cell entry. Recently, a Toxoplasma gondii rhomboid was also implicated in an intracellular signalling mechanism leading to parasite proliferation. In Entamoeba histolytica, the capacity to adhere to host cells and to phagocytose cells is potentiated by a rhomboid-like protease. Survey of a small number of protozoan parasite genomes has uncovered species-specific rhomboidlike protease genes, many of which are predicted to encode inactive enzymes. Functional investigation of the rhomboid-like proteases in other protozoan parasites will likely uncover novel and unexpected implications for this family of proteases.

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“…The cleavage of TgMICs by the Drosophila enzyme provided the evidence in support of MPP1 being a rhomboid-like protease (Urban & Freeman, 2003). T. gondii possesses six rhomboid-like proteins that belong to the family of intramembrane-cleaving serine proteases and TgROM4 sand TgROM5 constitute the two primary candidates for MPP1 activity (Brossier et al, 2005;Dowse et al, 2005). Indeed MPP1 was anticipated to be constitutively active at the parasite surface.…”

mentioning

confidence: 99%

Molecular dissection of host cell invasion by the Apicomplexans: the glideosome

Soldati‐Favre

2008

Parasite

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Summary :Gliding motility is an essential and fascinating apicomplexantypical adaptation to an intracellular lifestyle. Apicomplexan parasites rely on gliding motility for their migration across biological barriers and for host cell invasion and egress. This unusual substrate-dependent mode of locomotion involves the concerted action of secretory adhesins, a myosin motor, factors regulating actin dynamics and proteases. During invasion, complexes of soluble and transmembrane micronemes proteins (MICs) and rhoptry neck proteins (RONs) are discharged to the apical pole of the parasite, some protein acts as adhesins and bind to host cell receptors whereas others are involved in the moving junction formation. These complexes redistribute towards the posterior pole of the parasite via a physical connection to the parasite actomyosin system and are eventually released from the parasite surface by the action of parasite proteases.

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Apicomplexan rhomboids have a potential role in microneme protein cleavage during host cell invasion

Cited by 112 publications

References 46 publications

A Conserved Molecular Motor Drives Cell Invasion and Gliding Motility across Malaria Life Cycle Stages and Other Apicomplexan Parasites

A Conserved Molecular Motor Drives Cell Invasion and Gliding Motility across Malaria Life Cycle Stages and Other Apicomplexan Parasites

New insights into parasite rhomboid proteases

Molecular dissection of host cell invasion by the Apicomplexans: the glideosome

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