Abstract
Apicomplexan parasites including Toxoplasma gondii and Plasmodium spp. manufacture a complex arsenal of secreted proteins used to interact with and manipulate their host environment. These proteins are organised into three principle exocytotic compartment types according to their functions: micronemes for extracellular attachment and motility, rhoptries for host cell penetration, and dense granules for subsequent manipulation of the host intracellular environment. The order and timing of these events during the parasite's invasion cycle dictates when exocytosis from each compartment occurs. Tight control of compartment secretion is, therefore, an integral part of apicomplexan biology. Control of microneme exocytosis is best understood, where cytosolic intermediate molecular messengers cGMP and Ca2+ act as positive signals. The mechanisms for controlling secretion from rhoptries and dense granules, however, are virtually unknown. Here, we present evidence that dense granule exocytosis is negatively regulated by cytosolic Ca2+, and we show that this Ca2+‐mediated response is contingent on the function of calcium‐dependent protein kinases TgCDPK1 and TgCDPK3. Reciprocal control of micronemes and dense granules provides an elegant solution to the mutually exclusive functions of these exocytotic compartments in parasite invasion cycles and further demonstrates the central role that Ca2+ signalling plays in the invasion biology of apicomplexan parasites.
Highlights
Apicomplexan parasites comprise a large phylum of primarily obligate intracellular parasites of humans and animals that have a significant impact on human health and livestock production
Our data consistently indicate that Ca2+ has a role in negatively controlling granule proteins (GRAs) secretion, providing a reciprocal control mechanism to that of microneme proteins (MICs) secretion in extracellular parasites
Given our data that GRA secretion negatively correlates with cytosolic Ca2+ level increase, we tested if TgCDPK1 and/or 3 might be involved in regulating dense granule exocytosis
Summary
Apicomplexan parasites comprise a large phylum of primarily obligate intracellular parasites of humans and animals that have a significant impact on human health and livestock production. Control of secretion from micronemes is critical for the extracellular stages of the Toxoplasma infection cycle, control of rhoptry release for the invasion events, and control of dense granule release for the establishment and maintenance of the host cell environment for the parasite. In Plasmodium berghei, PKG acts upon phosphoinositide metabolism that releases inositol (1,4,5)‐ trisphosphate (IP3) from diacylglycerol (DAG), and IP3 releases Ca2+ stores in many systems (Brochet et al, 2014; Schlossmann et al, 2000) This phospholipid metabolism, notably DAG to phosphatidic acid (PA) interchange, has been shown to contribute directly to microneme docking at the plasma membrane in Toxoplasma, further implicating cGMP‐controlled events in MIC release (Bullen et al, 2016). Our data consistently indicate that Ca2+ has a role in negatively controlling GRA secretion, providing a reciprocal control mechanism to that of MIC secretion in extracellular parasites
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