Phosphatidic Acid-Mediated Signaling Regulates Microneme Secretion in Toxoplasma

Bullen, Hayley E; Jia, Yonggen; Yamaryo‐Botté, Yoshiki; Bisio, Hugo; Zhang, Ou; Jemelin, Natacha Klages; Marq, Jean Baptiste; Carruthers, Vern B.; Botté, Cyrille Y.; Soldati‐Favre, Dominique

doi:10.1016/j.chom.2016.02.006

Cited by 151 publications

(227 citation statements)

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“…Both micronemal proteins co-localized with the microneme markers MIC8 (Kessler et al, 2008) and PLP1 (Kafsack et al, 2009) (Figure 4E). ICAP1 was shown to be essential for regulated exocytosis during the preparation of this work (Bullen et al, 2016), confirming our predictions regarding its importance and localization.…”

Section: Resultssupporting

confidence: 87%

A Genome-wide CRISPR Screen in Toxoplasma Identifies Essential Apicomplexan Genes

Sidik

Huet

Ganesan

et al. 2016

Cell

742

108

1,001

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SUMMARY Apicomplexan parasites are leading causes of human and livestock diseases—like malaria and toxoplasmosis—yet most of their genes remain uncharacterized. Here, we present the first genome-wide genetic screen of an apicomplexan. We adapted CRISPR/Cas9 to assess the contribution of each gene from the human parasite Toxoplasma gondii during infection of fibroblasts. Our analysis defines ~200 previously uncharacterized, fitness-conferring genes unique to the phylum, from which 16 were investigated, revealing essential functions during infection of human cells. Secondary screens identify as an invasion factor the claudin-like apicomplexan microneme protein (CLAMP), which resembles mammalian tight-junction proteins and localizes to secretory organelles, making it critical to the initiation of infection. CLAMP is present throughout sequenced apicomplexan genomes, and is essential during the asexual stages of the malaria parasite Plasmodium falciparum. These results provide broad-based functional information on T. gondii genes and will facilitate future approaches to expand the horizon of antiparasitic interventions.

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Section: Resultssupporting

confidence: 87%

A Genome-wide CRISPR Screen in Toxoplasma Identifies Essential Apicomplexan Genes

Sidik

Huet

Ganesan

et al. 2016

Cell

742

108

1,001

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“…cGMP-dependent protein kinase (PKG) triggers microneme secretion and parasite egress in a calcium-independent manner 153,[157][158][159] . Recently, phosphatidic acid has been identified as an important lipid mediator of microneme secretion that acts in parallel to calcium 160 . The production of inositol-1,4,5-triphosphate by phosphatidylinositol phospholipase C (PI-PLC) and the concurrent calcium mobilization that occurs before microneme secretion are linked to the generation of diacylglycerol (DAG).…”

Section: Signalling and Gliding Motilitymentioning

confidence: 99%

“…The production of inositol-1,4,5-triphosphate by phosphatidylinositol phospholipase C (PI-PLC) and the concurrent calcium mobilization that occurs before microneme secretion are linked to the generation of diacylglycerol (DAG). DAG can be interconverted to phosphatidic acid through the action of diacylglycerol kinase 1 (DGK1) 160 . The relevance of phosphatidic acid is linked to acylated pleckstrin homology domaincontaining protein (APH), which is present at the surface of micronemes, conserved across the Apicomplexa phylum and acts as phosphatidic acid-detecting protein.…”

Section: Signalling and Gliding Motilitymentioning

confidence: 99%

“…Notably, the conditional depletion of TgAPH leads to a severe block in microneme secretion and consequently to an abrogation of the function of the glideosome 160 . In addition, a C2 domains-containing protein DOC2.1, which is also conserved across the apicomplexans, mediates apical microneme exocytosis in a calciumdependent manner 161 .…”

Section: Signalling and Gliding Motilitymentioning

confidence: 99%

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Gliding motility powers invasion and egress in Apicomplexa

et al. 2017

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| Protozoan parasites have developed elaborate motility systems that facilitate infection and dissemination. For example, amoebae use actin-rich membrane extensions called pseudopodia, whereas Kinetoplastida are propelled by microtubule-containing flagella. By contrast, the motile and invasive stages of the Apicomplexa -a phylum that contains the important human pathogens Plasmodium falciparum (which causes malaria) and Toxoplasma gondii (which causes toxoplasmosis) -have a unique machinery called the glideosome, which is composed of an actomyosin system that underlies the plasma membrane. The glideosome promotes substrate-dependent gliding motility, which powers migration across biological barriers, as well as active host cell entry and egress from infected cells. In this Review, we discuss the discovery of the principles that govern gliding motility, the characterization of the molecular machinery involved, and its impact on parasite invasion and egress from infected cells. NATURE REVIEWS | MICROBIOLOGYADVANCE ONLINE PUBLICATION | 1 REVIEWS © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d . ToxoplasmosisA food-borne infection caused by the parasite Toxoplasma gondii. The infection is usually mild or even asymptomatic, but can have serious consequences in patients who are immunocompromised and for the fetus in the case of primary infection during pregnancy. SporozoitesThe infectious and motile stage produced in oocysts and transmitted by the definitive host. TachyzoitesThe motile and fast-replicative stage of Toxoplasma gondii that is able to invade any nucleated cell in the host. MerozoitesThe stage of Plasmodium spp. that infects erythrocytes, in which it initiates a new asexual life cycle. Actomyosin systemA complex that comprises actin filaments, myosin and associated proteins, and that is involved in movement. GlideosomeA molecular complex that powers gliding motility in apicomplexan parasites.motility, invasion and egress. In this Review, we focus primarily on the T. gondii tachyzoite, for which functional studies were first carried out, and we compare and contrast this with the motile stages of malaria parasites -the sporozoite, merozoite and ookinete.Emergence of the capping model The motility of Apicomplexa (historically named Sporozoa) has caught the attention of scientists for more than a century 8 and was named gliding motility early on, on the basis of microscopic observations Nature Reviews | Microbiology www.nature.com/nrmicro © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d . of live specimens (FIG. 2; Supplementary information S1-S5 (movies)). This mode of motility differs substantially to amoeboid motion involving pseudopods, and from the ciliary and flagellar motion used by most unicellular organisms. The main hypothesis to explain gliding motility in the early days was slime secretion, as seen in slugs; ...

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“…Another established role for PA in secretion relates to the induction of neutrophil exocytosis from azurophilic granules by anti-neutrophil cytoplasmic antibodies (Williams et al, 2007). Moreover, the ability of apicomplexan parasites to invade and later exit infected cells relies on specialized organelles termed micronemes that release their contents including adhesins, perforins and proteases in a PA-dependent manner (Bullen et al, 2016).…”

Section: Pa Is Involved In Neurosecretionmentioning

confidence: 99%

Different species of phosphatidic acid are produced during neuronal growth and neurosecretion

Tanguy

Wang

Bagneaux

et al. 2018

OCL

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-Although originally restricted to their structural role as major constituents of membranes, lipids are now well-defined actors to integrate intracellular or extracellular signals. Accordingly, it has been known for decades that lipids, especially those coming from diet, are important to maintain normal physiological functions and good health. This is especially the case to maintain proper cognitive functions and avoid neuronal degeneration. But besides this empiric knowledge, the exact molecular nature of lipids in cellular signaling, as well as their precise mode of action are only starting to emerge. The recent development of novel pharmacological, molecular, cellular and genetic tools to study lipids in vitro and in vivo has contributed to this improvement in our knowledge. Among these important lipids, phosphatidic acid (PA) plays a unique and central role in a great variety of cellular functions. This article will review the different findings illustrating the involvement of PA generated by phospholipase D (PLD) and diacylglycerol kinases (DGK) in the different steps of neuronal development and neurosecretion. We will also present lipidomic evidences indicating that different species of PA are synthesized during these two key neuronal phenomena.Keywords: exocytosis / neuroendocrine / neuron / phospholipase D / phosphatidic acid Résumé -Différentes formes d'acide phosphatidique sont produites au cours de la croissance neuronale et la neurosécrétion. Bien qu'originalement restreints à leur rôle majeur de constituants principaux des membranes, il est maintenant communément admis que certains lipides possèdent également une fonction importante d'intégration des signaux intra-ou extra-cellulaires. En accord avec cette notion, cela fait des décennies qu'il est reconnu que les lipides, principalement via l'alimentation, jouent un rôle crucial dans le maintien de l'homéostasie de nombreuses fonctions physiologiques et dans la santé humaine au sens large. Ceci est particulièrement le cas pour la conservation d'un niveau optimal des fonctions cognitives et pour lutter contre la dégénérescence neuronale. Toutefois, malgré ces connaissances empiriques, la nature exacte des lipides impliqués, ainsi que les mécanismes d'action mis en jeu peinent à émerger. Le développement récent de nouveaux outils génétiques, moléculaires, et pharmacologiques pour étudier les lipides in vitro et in vivo permettent à présent d'améliorer nos connaissances. Parmi ces lipides, l'acide phosphatidique joue un rôle particulier et central dans diverses fonctions cellulaires essentielles. Cet article résume les observations récentes qui illustrent que l'acide phosphatidique, produit par deux voies enzymatiques distinctes impliquant les phospholipases D et les diacylglycérol-kinases, est impliqué dans le développement neuronal et la neurosécrétion. Pour finir, nous présentons des résultats d'analyses lipidomiques qui indiquent que différentes formes de l'acide phosphatidique sont produites au cours de ces deux processus neuronaux majeur...

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Phosphatidic Acid-Mediated Signaling Regulates Microneme Secretion in Toxoplasma

Cited by 151 publications

References 40 publications

A Genome-wide CRISPR Screen in Toxoplasma Identifies Essential Apicomplexan Genes

A Genome-wide CRISPR Screen in Toxoplasma Identifies Essential Apicomplexan Genes

Gliding motility powers invasion and egress in Apicomplexa

Different species of phosphatidic acid are produced during neuronal growth and neurosecretion

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