A Forward Genetic Screen Reveals that Calcium-dependent Protein Kinase 3 Regulates Egress in Toxoplasma

Garrison, Erin; Treeck, Moritz; Ehret, Emma; Butz, Heidi A.; Garbuz, Tamila; Oswald, Benji P.; Settles, Matthew L.; Boothroyd, John C.; Arrizabalaga, Gustavo

doi:10.1371/journal.ppat.1003049

Cited by 126 publications

(178 citation statements)

References 59 publications

(101 reference statements)

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“…TgCDPK3 is localised to the PM and the first 15 N-terminal amino acids are sufficient for this targeting (Garrison et al, 2012;Lourido et al, 2012;McCoy et al, 2012). Mutations in the acylation sites hampered complementation of a knockout strain (Garrison et al, 2012;McCoy et al, 2012), thus confirming that lipid anchoring to the membrane is essential for the function of TgCDPK3 in parasite egress from infected cells.…”

Section: Calcium Signallingmentioning

confidence: 98%

“…Among these 112 proteins, some kinases (CDPK3, CDPK4, PKG), gliding-associated proteins (GAP45, GAP70 and GAP80), inner membrane complex (IMC) sub-compartment proteins (ISP1, 2 and 3) and the rhoptryassociated protein with armadillo repeats only protein (ARO) were found. These proteins are probably truly acylated, since most of them become cytosolic after mutation of the predicted modified residues (Beck et al, 2010Garrison et al, 2012;Lourido et al, 2012;McCoy et al, 2012;Mueller et al, 2013). Many of these proteins are broadly conserved across the phylum Apicomplexa and for some of them, palmitoylation is essential for their function.…”

Section: Acylation Impacts On the Fate Of Proteinsmentioning

confidence: 99%

Section: Calcium Signallingmentioning

confidence: 99%

“…Two of these, TgCDPK3 and TgCDPK4, are predicted to be myristoylated and palmitoylated and TgCDPK3 has been linked to egress, notably via the identification of several mutations in the corresponding locus that cause resistance to calcium ionophore-induced egress (Garrison et al, 2012). TgCDPK3 is localised to the PM and the first 15 N-terminal amino acids are sufficient for this targeting (Garrison et al, 2012;Lourido et al, 2012;McCoy et al, 2012). Mutations in the acylation sites hampered complementation of a knockout strain (Garrison et al, 2012;McCoy et al, 2012), thus confirming that lipid anchoring to the membrane is essential for the function of TgCDPK3 in parasite egress from infected cells.…”

Section: Calcium Signallingmentioning

confidence: 99%

“…Very little is known about lipid modification in apicomplexans, however palmitoylation appears to be widely used by these parasites. The functional importance of palmitoylation for the lytic cycle of T. gondii has recently been highlighted by a series of striking examples of palmitoylated substrates critically involved in diverse processes such as motility, invasion (Gaskins et al, 2004;Frenal et al, 2010), calcium signalling (Garrison et al, 2012;Lourido et al, 2012;McCoy et al, 2012), organelle positioning Mueller et al, 2013) and parasite division (Beck et al, 2010). Importantly, these cases implicate proteins that are broadly conserved across the phylum Apicomplexa.…”

Section: Introductionmentioning

confidence: 99%

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Emerging roles for protein S-palmitoylation in Toxoplasma biology

Frénal

Kemp

Soldati‐Favre

2014

International Journal for Parasitology

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a b s t r a c tPost-translational modifications are refined, rapidly responsive and powerful ways to modulate protein function. Among post-translational modifications, acylation is now emerging as a widespread modification exploited by eukaryotes, bacteria and viruses to control biological processes. Protein palmitoylation involves the attachment of palmitic acid, also known as hexadecanoic acid, to cysteine residues of integral and peripheral membrane proteins and increases their affinity for membranes. Importantly, similar to phosphorylation, palmitoylation is reversible and is becoming recognised as instrumental for the regulation of protein function by modulating protein interactions, stability, folding, trafficking and signalling. Palmitoylation appears to play a central role in the biology of the Apicomplexa, regulating critical processes such as host cell invasion which is vital for parasite survival and dissemination. The recent identification of over 400 palmitoylated proteins in Plasmodium falciparum erythrocytic stages illustrates the broad spread and impact of this modification on parasite biology. The main enzymes responsible for protein palmitoylation are multi-membrane protein S-acyl transferases harbouring a catalytic Asp-HisHis-Cys (DHHC) motif. A global functional analysis of the repertoire of protein S-acyl transferases in Toxoplasma gondii and Plasmodium berghei has recently been performed. The essential nature of some of these enzymes illustrates the key roles played by this post-translational modification in the corresponding substrates implicated in fundamental processes such as parasite motility and organelle biogenesis. Toward a better understanding of the depalmitoylation event, a protein with palmitoyl protein thioesterase activity has been identified in T. gondii. TgPPT1/TgASH1 is the main target of specific acyl protein thioesterase inhibitors but is dispensable for parasite survival, suggesting the implication of other genes in depalmitoylation. Palmitoylation/depalmitoylation cycles are now emerging as potential novel regulatory networks and T. gondii represents a superb model organism in which to explore their significance.

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Section: Calcium Signallingmentioning

confidence: 98%

Section: Acylation Impacts On the Fate Of Proteinsmentioning

confidence: 99%

Section: Calcium Signallingmentioning

confidence: 99%

Section: Calcium Signallingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Emerging roles for protein S-palmitoylation in Toxoplasma biology

Frénal

Kemp

Soldati‐Favre

2014

International Journal for Parasitology

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A central role for phosphatidic acid as a lipid mediator of regulated exocytosis in apicomplexa

Bullen

Soldati‐Favre

2016

FEBS Letters

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Edited by Wilhelm JustLipids are commonly known for the structural roles they play, however, the specific contribution of different lipid classes to wide-ranging signalling pathways is progressively being unravelled. Signalling lipids and their associated effector proteins are emerging as significant contributors to a vast array of effector functions within cells, including essential processes such as membrane fusion and vesicle exocytosis. Many phospholipids have signalling capacity, however, this review will focus on phosphatidic acid (PA) and the enzymes implicated in its production from diacylglycerol (DAG) and phosphatidylcholine (PC): DGK and PLD respectively. PA is a negatively charged, coneshaped lipid identified as a key mediator in specific membrane fusion and vesicle exocytosis events in a variety of mammalian cells, and has recently been implicated in specialised secretory organelle exocytosis in apicomplexan parasites. This review summarises the recent work implicating a role for PA regulation in exocytosis in various cell types. We will discuss how these signalling events are linked to pathogenesis in the phylum Apicomplexa.

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The Role of Host‐ and Parasite‐Encoded Kinases inToxoplasma–Host Interactions

Blader¹,

Arrizabalaga²,

Sullivan³

2013

Protein Phosphorylation in Parasites

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Over the past few years a common theme has emerged in which microbial pathogens grow and cause disease by either expressing their own repertoire of kinases, or by regulating the activity of host-encoded kinases. Toxoplasma gondii is an obligate intracellular parasite that is capable of infecting most nucleated cell types in warm-blooded animals. Within its intermediate hosts, T. gondii exists as two interconvertable stages: dormant bradyzoites, and replicative disease-causing tachyzoites. Tachyzoite growth is achieved by a lytic cycle that is composed of repeated rounds of parasite invasion, replication, and egress. Each of these steps requires the coordinated activity of host and parasite-encoded kinases. In addition to the parasite's lytic cycle, T. gondii-encoded kinases and related pseudokinases that are secreted into the host cell have been identified as key virulence factors. These findings will be highlighted in this chapter, and emerging questions will be discussed.

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A Forward Genetic Screen Reveals that Calcium-dependent Protein Kinase 3 Regulates Egress in Toxoplasma

Cited by 126 publications

References 59 publications

Emerging roles for protein S-palmitoylation in Toxoplasma biology

Emerging roles for protein S-palmitoylation in Toxoplasma biology

A central role for phosphatidic acid as a lipid mediator of regulated exocytosis in apicomplexa

The Role of Host‐ and Parasite‐Encoded Kinases inToxoplasma–Host Interactions

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