A spatially localized rhomboid protease cleaves cell surface adhesins essential for invasion by
            <i>Toxoplasma</i>

Brossier, Fabien; Jewett, Travis J.; Sibley, L. David; Urban, Siniša

doi:10.1073/pnas.0407918102

Cited by 188 publications

(261 citation statements)

References 35 publications

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“…It was also shown that TgROM5 redistributes to the posterior of the parasite upon microneme secretion. This led to the conclusion that TgROM5 is responsible for MPP1 activity (Brossier et al, 2005). The discrepancy between this study and the results reported here might be explained by the use of different cell lines and constructs for the cleavage assays.…”

Section: Discussioncontrasting

confidence: 94%

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

Dowse

Pascall

Brown

et al. 2005

International Journal for Parasitology

112

130

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Apicomplexan parasites secrete transmembrane (TM) adhesive proteins as part of the process leading to host cell attachment and invasion. These microneme proteins are cleaved in their TM domains by an unidentified protease termed microneme protein protease 1 (MPP1). The cleavage site sequence (IAYGG), mapped in the Toxoplasma gondii microneme proteins TgMIC2 and TgMIC6, is conserved in microneme proteins of other apicomplexans including Plasmodium species. We report here the characterisation of novel T. gondii proteins belonging to the rhomboid family of intramembrane-cleaving serine proteases. T. gondii possesses six genes encoding rhomboid-like proteins. Four are localised along the secretory pathway and therefore constitute possible candidates for MPP1 activity. Toxoplasma rhomboids TgROM1, TgROM2 and TgROM5 cleave the TM domain of Drosophila Spitz, an established substrate for rhomboids from several species, demonstrating that they are active proteases. In addition, TgROM2 cleaves chimeric proteins that contain the TM domains of TgMIC2 and TgMIC12. q

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Section: Discussioncontrasting

confidence: 94%

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

Dowse

Pascall

Brown

et al. 2005

International Journal for Parasitology

112

130

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“…Apicomplexan rhomboid proteases have been implicated to play an important role in host cell invasion (10,11). PfROM1 substrates have been identified in P. falciparum by using a mammalian cell-based proteolytic assay (12) that identified various micronemal proteins as potential substrates including AMA1.…”

mentioning

confidence: 99%

Mononeme: A new secretory organelle in Plasmodium falciparum merozoites identified by localization of rhomboid-1 protease

Singh

Plassmeyer

Gaur

et al. 2007

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

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Compartmentalization of proteins into subcellular organelles in eukaryotic cells is a fundamental mechanism of regulating complex cellular functions. Many proteins of Plasmodium falciparum merozoites involved in invasion are compartmentalized into apical organelles. We have identified a new merozoite organelle that contains P. falciparum rhomboid-1 (PfROM1), a protease that cleaves the transmembrane regions of proteins involved in invasion. By immunoconfocal microscopy, PfROM1 was localized to a single, thread-like structure on one side of the merozoites that appears to be in close proximity to the subpellicular microtubules. PfROM1 was not found associated with micronemes, rhoptries, or dense granules, the three identified secretory organelles of invasion. Release of merozoites from schizonts resulted in the movement of PfROM1 from the lateral asymmetric localization to the merozoite apical pole and the posterior pole. We have named this single thread-like organelle in merozoites, the mononeme. malaria A picomplexa are named for a set of secretory organelles (rhoptries, micronemes, and dense granules) found at the apical end of these parasites, the end that invades cells in the vertebrate host (1). These organelles were first identified by their distinct morphological appearances in transmission electron microscopy (2-4). Many parasite proteins required for invasion of erythrocytes are segregated into the micronemes (5, 6). For example, Plasmodium falciparum apical membrane antigen 1 (AMA1) is held in the micronemes in merozoites inside of erythrocytes. Release from the erythrocyte triggers the movement of AMA1 to the cell surface where it functions in invasion (7,8). Similarly, rhoptries sequester a different set of proteins and their contents are released onto the erythrocyte surface (4, 9), presumably to break the local cytoskeleton and to initiate formation of the parasitophorous vacuole. Taken together, these observations provide evidence for compartmentalization of parasite proteins into distinct organelles with related functions in invasion. Presumably, such compartmentalization provides a mechanism for orchestrating the timing of delivery or activity of the proteins during the complex process of invasion.Apicomplexan rhomboid proteases have been implicated to play an important role in host cell invasion (10, 11). PfROM1 substrates have been identified in P. falciparum by using a mammalian cell-based proteolytic assay (12) that identified various micronemal proteins as potential substrates including AMA1. Because AMA1 has been implicated as essential for invasion, separation of PfROM1 from this substrate within the parasite may be important to prevent premature cleavage. Studies defining the spatiotemporal distribution of PfROM1 in P. falciparum merozoites are, therefore, likely to contribute to a clearer understanding of its role in erythrocyte invasion. Expression of hemagglutinin (HA)-tagged P. falciparum rhomboid-1 (PfROM1) localizes it to a new subcellular compartment distinct from other known meroz...

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“…Additional studies identified the Toxoplasma rhomboids required for key cleavage events during host cell invasion and intracellular growth (Zhou et al 2004;Brossier et al 2005Brossier et al , 2008. Similar rhomboids have been found in all other apicomplexans for which genomic sequences are available, including Cryptosporidium and Plasmodium species (Dowse and Soldati 2005), where they appear to play similar roles (O'Donnell et al 2006;Singh et al 2007).…”

Section: Rhomboidmentioning

confidence: 58%

“…Although originally recognized as a widespread mechanism of signal transduction, recent findings expand its roles to other cellular functions. In apicomplexans like T. gondii and P. falciparum, rhomboids participate in the active invasion of host cells by cleaving adhesins and are thus essential for these obligate intracellular parasites (Brossier et al 2005(Brossier et al , 2008Baker et al 2006).…”

Section: Resultsmentioning

confidence: 99%

Intriguing parasites and intramembrane proteases: Figure 1.

Rawson

2008

Genes Dev.

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Rhomboid intramembrane proteases occur throughout the kingdoms of life. In this issue of Genes & Development, Baxt and colleagues (pp. 1636-1646) report that the single proteolytic rhomboid (EhROM1) from Entamoeba histolytica cleaves cell surface galactose-binding or N-acetylgalactosamine-binding (Gal/Gal-NAc) lectins. EhROM1 and lectins colocalize during phagocytosis and receptor capping. EhROM1 is found at the base of the cap rather than in the cap proper, suggesting a role in receptor shedding and implying that EhROM1 is crucial for amoebal infection.Parasitic protists are fascinating organisms in their own right, with their typically complex life cycles, distinctive physiologies, and uncertain relationships. They are of immense practical interest as well; parasitic infections account for an enormous proportion of the disease burden on the human population worldwide. The debilitating and often lethal parasitic diseases remain among the most intractable infections and result in between 1.5 and 3 million deaths annually. The enormous costs resulting from lost productivity and caring for the millions who suffer from parasitic disease represent significant hurdles to economic development throughout the world, and these burdens tend to be the highest where the resources to bear them are the least. Advances in our understanding of parasites, such as how they initiate and maintain infections, therefore, have significant potential to improve human health and well-being worldwide.Among parasitic diseases, amoebiasis ranks second only to malaria in global morbidity, affecting vast numbers of people worldwide and killing some 100,000 annually (World Health Organization 1997). The causative agent of human amoebiasis, Entamoeba histolytica, faces many of the same challenges faced by other parasites when establishing infection. Baxt et al. (2008) detail the role of the single rhomboid intramembrane protease from E. histolytica in crucial parasite processes: phagocytosis and immune evasion. The parasitic lifestyleParasitism poses common challenges to the diverse organisms that practice it. Parasites must first locate and enter a host. Next, in many cases, host tissues or cells must be invaded, requiring some means of attachment and introgression. The successful parasite usually establishes a long-term infection, and this potentially affords the host ample time to mount a vigorous immune response to the invader. In order to survive and reproduce while "dining at another's table," the parasite must somehow manage to evade host immune defenses that may act at several stages of the infection cycle. Broadly, extracellular parasites are subject to the humoral response, while intracellular stages are the target of cellular immunity. Invasion and evasionStrategies for evading the host immune response are as complex and varied as the parasites that use them, and most parasites use several different strategies in the course of infection. Parasites may engage various responses to the host immune system (Zambrano-Villa et al. 2002). So...

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A spatially localized rhomboid protease cleaves cell surface adhesins essential for invasion by Toxoplasma

Cited by 188 publications

References 35 publications

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

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

Mononeme: A new secretory organelle in Plasmodium falciparum merozoites identified by localization of rhomboid-1 protease

Intriguing parasites and intramembrane proteases: Figure 1.

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