A Member of the Ferlin Calcium Sensor Family Is Essential for Toxoplasma gondii Rhoptry Secretion

Coleman, Bradley I.; Saha, Sudeshna; Sato, Seiko; Engelberg, Klemens; Ferguson, David J. P.; Coppens, Isabelle; Lodoen, Melissa B.; Gubbels, Marc‐Jan

doi:10.1128/mbio.01510-18

Cited by 43 publications

(58 citation statements)

References 65 publications

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“…The signaling cascade leading to rhoptry secretion is still unknown, nevertheless a recent study showed that parasites conditionally depleted for FER2, a Ca 2+ sensor belonging to the ferlin family, are unable to discharge the rhoptries. This suggests that rhoptry secretion might also be driven by Ca 2+ signaling . Even though valuable advances have been made toward a better understanding of the rhoptry and microneme membrane fusion mechanisms, little is known about the docking and transport of these secretory organelles to the site of fusion at the tip of the parasite.…”

Section: Introductionmentioning

confidence: 99%

The roles of Centrin 2 and Dynein Light Chain 8a in apical secretory organelles discharge of Toxoplasma gondii

Lentini

Dubois

Maco

et al. 2019

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To efficiently enter host cells, apicomplexan parasites such as Toxoplasma gondii rely on an apical complex composed of tubulin‐based structures as well as two sets of secretory organelles named micronemes and rhoptries. The trafficking and docking of these organelles to the apical pole of the parasite is crucial for the discharge of their contents. Here, we describe two proteins typically associated with microtubules, Centrin 2 (CEN2) and Dynein Light Chain 8a (DLC8a), that are required for efficient host cell invasion. CEN2 localizes to four different compartments, and remarkably, conditional depletion of the protein occurs in stepwise manner, sequentially depleting the protein pools from each location. This phenomenon allowed us to discern the essential function of the apical pool of CEN2 for microneme secretion, motility, invasion and egress. DLC8a localizes to the conoid, and its depletion also perturbs microneme exocytosis in addition to the apical docking of the rhoptry organelles, causing a severe defect in host cell invasion. Phenotypic characterization of CEN2 and DLC8a indicates that while both proteins participate in microneme secretion, they likely act at different steps along the cascade of events leading to organelle exocytosis.

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Section: Introductionmentioning

confidence: 99%

The roles of Centrin 2 and Dynein Light Chain 8a in apical secretory organelles discharge of Toxoplasma gondii

Lentini

Dubois

Maco

et al. 2019

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“…SDS-PAGE (8–12%, MOPS) separated ESA samples and corresponding total parasite lysates were blotted onto PVDF membrane and probed with mouse α-MIC2 (1:8000) [ 57 ], mouse α-TY (MAb BB2; 1:1000; a kind gift from Sebastian Lourido), mouse α-tubulin (12G10) (1:2000; Developmental Studies Hybridoma Bank, Iowa City, IA, USA), rabbit α-GRA7 (1:2000; a gift from John Boothroyd) [ 58 ]. Procedures and signal intensity quantification as previously described [ 43 , 47 ]. A two-tailed, two sample equal variance Student’s t -test was performed on protein levels normalized to α-tubulin.…”

Section: Methodsmentioning

confidence: 99%

Ferlins and TgDOC2 in Toxoplasma Microneme, Rhoptry and Dense Granule Secretion

Tagoe

Drozda

Falco

et al. 2021

Life

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The host cell invasion process of apicomplexan parasites like Toxoplasma gondii is facilitated by sequential exocytosis of the microneme, rhoptry and dense granule organelles. Exocytosis is facilitated by a double C2 domain (DOC2) protein family. This class of C2 domains is derived from an ancestral calcium (Ca2+) binding archetype, although this feature is optional in extant C2 domains. DOC2 domains provide combinatorial power to the C2 domain, which is further enhanced in ferlins that harbor 5–7 C2 domains. Ca2+ conditionally engages the C2 domain with lipids, membranes, and/or proteins to facilitating vesicular trafficking and membrane fusion. The widely conserved T. gondii ferlins 1 (FER1) and 2 (FER2) are responsible for microneme and rhoptry exocytosis, respectively, whereas an unconventional TgDOC2 is essential for microneme exocytosis. The general role of ferlins in endolysosmal pathways is consistent with the repurposed apicomplexan endosomal pathways in lineage specific secretory organelles. Ferlins can facilitate membrane fusion without SNAREs, again pertinent to the Apicomplexa. How temporal raises in Ca2+ combined with spatiotemporally available membrane lipids and post-translational modifications mesh to facilitate sequential exocytosis events is discussed. In addition, new data on cross-talk between secretion events together with the identification of a new microneme protein, MIC21, is presented.

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“…In T. gondii, MIC8 appears to participate in rhoptry secretion (Kessler et al, 2008), while in Plasmodium, the interaction of the microneme adhesin EBA175 with its receptor glycophorin A decreases cytosolic Ca 2+ levels in merozoites and triggers rhoptry secretion (Singh et al, 2010). A cytoplasmic protein homologous to the ferlin family of Ca 2+ -sensing proteins (TgFER2) has been shown to be essential in rhoptry secretion in T. gondii and points to a role for Ca 2+ signaling in the secretion of this organelle during invasion (Coleman et al, 2018). In addition, a newly identified set of proteins termed rhoptry apical surface proteins (RASPs) appear to be essential for rhoptry secretion in both T. gondii and P. falciparum by promoting the rhoptry fusion with parasite PM in a Ca 2+ -independent manner (Suarez et al, 2019).…”

Section: Box 2 Apicomplexansmicroneme and Rhoptry Secretion And Glidmentioning

confidence: 99%

Cell invasion by intracellular parasites – the many roads to infection

Horta

Andrade

Martins‐Duarte

et al. 2020

Journal of Cell Science

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Intracellular parasites from the genera Toxoplasma, Plasmodium, Trypanosoma, Leishmania and from the phylum Microsporidia are, respectively, the causative agents of toxoplasmosis, malaria, Chagas disease, leishmaniasis and microsporidiosis, illnesses that kill millions of people around the globe. Crossing the host cell plasma membrane (PM) is an obstacle these parasites must overcome to establish themselves intracellularly and so cause diseases. The mechanisms of cell invasion are quite diverse and include (1) formation of moving junctions that drive parasites into host cells, as for the protozoans Toxoplasma gondii and Plasmodium spp., (2) subversion of endocytic pathways used by the host cell to repair PM, as for Trypanosoma cruzi and Leishmania, (3) induction of phagocytosis as for Leishmania or (4) endocytosis of parasites induced by specialized structures, such as the polar tubes present in microsporidian species. Understanding the early steps of cell entry is essential for the development of vaccines and drugs for the prevention or treatment of these diseases, and thus enormous research efforts have been made to unveil their underlying biological mechanisms. This Review will focus on these mechanisms and the factors involved, with an emphasis on the recent insights into the cell biology of invasion by these pathogens.

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A Member of the Ferlin Calcium Sensor Family Is Essential for Toxoplasma gondii Rhoptry Secretion

Cited by 43 publications

References 65 publications

The roles of Centrin 2 and Dynein Light Chain 8a in apical secretory organelles discharge of Toxoplasma gondii

The roles of Centrin 2 and Dynein Light Chain 8a in apical secretory organelles discharge of Toxoplasma gondii

Ferlins and TgDOC2 in Toxoplasma Microneme, Rhoptry and Dense Granule Secretion

Cell invasion by intracellular parasites – the many roads to infection

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