Microneme Proteins in Apicomplexans

Carruthers, Vern B.; Tomley, Fiona M.

doi:10.1007/978-0-387-78267-6_2

Cited by 207 publications

(174 citation statements)

References 90 publications

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“…Microneme secretion is a carefully controlled and directed event that is calcium-regulated and occurs only at the apical end of the parasite. 16 This is analogous to the calciummediated and directed release of perforin from secretory lysosomes of natural killer cells and cytotoxic T lymphocytes and represents an effective mechanism to achieve a high local concentration of PLP monomers delivered to a limited area on the target membrane. 3,17 The majority of uncharacterized ApiPLPs are also likely to be secreted based on the presence of a secretory signal sequence (Fig.…”

Section: Structurementioning

confidence: 99%

Apicomplexan perforin-like proteins

Kafsack

Carruthers

2010

Communicative & Integrative Biology

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Section: Structurementioning

confidence: 99%

Apicomplexan perforin-like proteins

Kafsack

Carruthers

2010

Communicative & Integrative Biology

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“…Micronemes are specialized secretory vesicles present in all motile stages of apicomplexan parasites (reviewed in Ref. 2). The majority of internal microneme (MIC) 3 proteins (i.e.…”

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confidence: 99%

Serum Albumin Stimulates Protein Kinase G-dependent Microneme Secretion in Toxoplasma gondii

Brown

Lourido

Sibley

2016

Journal of Biological Chemistry

103

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Microneme secretion is essential for motility, invasion, and egress in apicomplexan parasites. Although previous studies indicate that Ca 2؉ and cGMP control microneme secretion, little is known about how these pathways are naturally activated. Here we have developed genetically encoded indicators for Ca 2؉ and microneme secretion to better define the signaling pathways that regulate these processes in Toxoplasma gondii. We found that microneme secretion was triggered in vitro by exposure to a single host protein, serum albumin. The natural agonist serum albumin induced microneme secretion in a protein kinase G-dependent manner that correlated with increased cGMP levels. Surprisingly, serum albumin acted independently of elevated Ca 2؉ and yet it was augmented by artificial agonists that raise Ca 2؉ , such as ethanol. Furthermore, although ethanol elevated intracellular Ca 2؉ , it alone was unable to trigger secretion without the presence of serum or serum albumin. This dichotomy was recapitulated by zaprinast, a phosphodiesterase inhibitor that elevated cGMP and separately increased Ca 2؉ in a protein kinase G-independent manner leading to microneme secretion. Taken together, these findings reveal that microneme secretion is centrally controlled by protein kinase G and that this pathway is further augmented by elevation of intracellular Ca 2؉ .Toxoplasma gondii is an important opportunistic pathogen and model organism for studying the biology of members of the phylum Apicomplexa (1). Micronemes are specialized secretory vesicles present in all motile stages of apicomplexan parasites (reviewed in Ref. 2). The majority of internal microneme (MIC) 3 proteins (i.e. cargo) consist of adhesive proteins that translocate to the surface of the parasite following the regulated fusion of the organelle with the apical plasma membrane.

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“…Micronemal adhesins contain a variety of extracellular adhesive domains, a transmembrane domain, and a short cytoplasmic tail that is rich in acidic residues and contains a tryptophan residue (Trp) at or near the extreme carboxyl terminus (3). These conserved features of the cytoplasmic tails are critical to their function, as shown by mutational studies and functional replacement of the thrombospondin-related adhesive protein (TRAP) tail (TRAPt) in P. berghei with the T. gondii Microneme Protein 2 (MIC2) tail (TgMIC2t) (4).…”

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confidence: 99%

Toxoplasmaaldolase is required for metabolism but dispensable for host-cell invasion

Shen

Sibley

2014

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

105

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Gliding motility and host-cell invasion by apicomplexan parasites depend on cell-surface adhesins that are translocated via an actinmyosin motor beneath the membrane. The current model posits that fructose-1,6-bisphosphate aldolase (ALD) provides a critical link between the cytoplasmic tails of transmembrane adhesins and the actin-myosin motor. Here we tested this model using the Toxoplasma gondii apical membrane protein 1 (TgAMA1), which binds to aldolase in vitro. TgAMA1 cytoplasmic tail mutations that disrupt ALD binding in vitro showed no correlation with host-cell invasion, indicating this interaction is not essential. Furthermore, ALD-depleted parasites were impaired when grown in glucose, yet they showed normal gliding and invasion in glucose-free medium. Depletion of ALD in the presence of glucose led to accumulation of fructose-1,6-bisphosphate, which has been associated with toxicity in other systems. Finally, TgALD knockout parasites and an ALD mutant that specifically disrupts adhesin binding in vitro also supported normal invasion when cultured in glucosefree medium. Taken together, these results suggest that ALD is primarily important for energy metabolism rather than interacting with microneme adhesins, challenging the current model for apicomplexan motility and invasion.micronemal adhesin | motor complex | glycolysis T he phylum Apicomplexa is a group of mostly intracellular parasites that contains a number of human pathogens, including Toxoplasma gondii and Plasmodium spp., the causative agent of malaria. As intracellular pathogens, efficient host-cell invasion is critical for survival, dissemination, and transmission of these parasites. Although they infect different types of host cells, apicomplexan parasites share a conserved mode of host-cell invasion that relies on regulated secretion of adhesive proteins and active motility that is powered by an actin-myosin motor complex (1, 2). According to the current model, motility and host-cell invasion depend on transmembrane adhesins that are secreted apically from the micronemes and translocated along the cell surface in a conveyor belt fashion, using the force generated by the motor complex beneath the parasite membrane (1, 2).Micronemal adhesins contain a variety of extracellular adhesive domains, a transmembrane domain, and a short cytoplasmic tail that is rich in acidic residues and contains a tryptophan residue (Trp) at or near the extreme carboxyl terminus (3). These conserved features of the cytoplasmic tails are critical to their function, as shown by mutational studies and functional replacement of the thrombospondin-related adhesive protein (TRAP) tail (TRAPt) in P. berghei with the T. gondii Microneme Protein 2 (MIC2) tail (TgMIC2t) (4). The cytoplasmic tails of several micronemal adhesins are thought to be anchored to the actin-myosin motor through a bridging molecule, the glycolytic enzyme fructose-1,6-bisphosphate aldolase (ALD) (5, 6). Mutational analysis has shown that in vitro binding of TgMIC2t and PbTRAPt to ALD is mediated by t...

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Microneme Proteins in Apicomplexans

Cited by 207 publications

References 90 publications

Apicomplexan perforin-like proteins

Apicomplexan perforin-like proteins

Serum Albumin Stimulates Protein Kinase G-dependent Microneme Secretion in Toxoplasma gondii

Toxoplasmaaldolase is required for metabolism but dispensable for host-cell invasion

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