The triumvirate of signaling molecules controlling Toxoplasma microneme exocytosis: Cyclic GMP, calcium, and phosphatidic acid

To elicit effective invasion and egress from infected cells, obligate intracellular parasites of the phylum Apicomplexa rely on the timely and spatially controlled exocytosis of specialized secretory organelles termed the micronemes.The effector molecules and signaling events underpinning this process are intricate; however, recent advances within the field of Toxoplasma gondii research have facilitated a broader understanding as well as a more integrated view of this complex cascade of events and have unraveled the importance of phosphatidic acid (PA) as a lipid mediator at multiple steps in this process. The signaling nodeAt any point during intracellular replication, deleterious environmental changes resulting in a loss of host-cell integrity can trigger T. gondii tachyzoite egress from infected cells via activation of microneme exocytosis and the actomyosin system.Extrinsic and intrinsic signals are likely to govern parasite egress from infected cells; however, the studies performed to date have implicated only specific extrinsic stimuli including low potassium (K + ), low pH [1, 2], and serum albumin [3].During the intracellular cycle, T. gondii tachyzoites are surrounded by a parasitophorous vacuole membrane (PVM), which is permeable to small molecules, and changes in K + or H + levels are sensed by the parasite through unknown mechanisms to promote microneme secretion.Interestingly, exposure to an acidic environment can overcome a high potassium-induced block in microneme exocytosis, implying that K + and pH are sensed by different receptors or that pH sensing is downstream of K + detection [2].These extrinsic signals feed into a pathway within which phosphoinositide-phospholipase C (PI-PLC) forms a signaling node, hydrolyzing phosphatidylinositol 4,5-bisphosphate (PI [4,5] P 2 ) to generate diacylglycerol (DAG) and inositol triphosphate (IP 3 ) to produce PA and to mobilize calcium, respectively, to ultimately trigger microneme exocytosis [4].Further feeding this pathway are diverse signaling events carried out by cyclic nucleotides (Fig 1 and Table 1).