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Expanding the Composition and Function of the Toxoplasma Inner Membrane Complex


The superphylum Alveolata contains three remarkably diverse groups of protozoans: the free-living ciliates and dinoflagellates, and the parasitic apicomplexans. Despite their diversity in morphology and lifestyle, alveolates are taxonomically unified by the presence of alveoli, a peripheral membrane system situated underneath the plasma membrane. The phylum Apicomplexa has received extensive attention due to the medical and economic burdens caused by its parasitic constituents, which include Toxoplasma gondii (toxoplasmosis) and Plasmodium spp.(malaria). Importantly, T. gondii serves as a model organism for these apicomplexans and even alveolates due to its experimental tractability. Moreover, toxoplasmosis is a life-threatening disease for immunocompromised individuals and congenitally infected neonates, highlighting the desperate need to understand its biology and develop better therapeutics against this pathogen.

A hallmark structure of the Alveolata is the alveoli, called the inner membrane complex (IMC) in apicomplexan parasites. The IMC is a peripheral membrane-cytoskeletal system underlying the plasma membrane and governs essential functions in all facets of the parasite’s intracellular lifestyle, including host cell invasion, replication, and egress. Specifically, it serves as a platform for the actin-myosin motor that powers gliding motility and provides a scaffold for daughter cells during replication. However, the sectioned organization of the IMC into multiple distinct subcompartments suggests additional functions not yet discovered for each compartment. Furthermore, even the well-established functions are not thoroughly understood, largely due to the scarcity of known IMC components. Here, we define a novel third role for the IMC and greatly expand the current catalog of daughter IMC proteins.

By characterizing the apical cap proteins AC9 and AC10, we demonstrate for the first time that the IMC apical cap critically stabilizes the apical complex, a cytoskeletal structure that controls parasite motility and secretory organelle exocytosis. We discover that AC9:AC10 performs this function by interacting with the MAP kinase ERK7 and concentrating it in the apical cap. Our subsequent dissection of the AC9:AC10:ERK7 complex revealed multiple independent interactions that organize the apical cap and uncovered an unusual mechanism of competitive inhibition that AC9 exerts on ERK7. This implicates the apical cap as not only an anchoring site for ERK7, but also as a regulatory center for its kinase activity.

We also explore the daughter cell scaffold by focusing on IMC29, pinpointing its precise timing of expression and describing its important function in coordinating the initiation stages of endodyogeny. We then use proximity labeling to identify a large array of novel IMC proteins, many of which localize exclusively to the nascent daughter cells. This firmly establishes the daughter IMC as a distinct subcompartment with its own cohort of proteins. Moreover, some of these proteins exhibited an interesting localization to the membrane interface between two daughter cells, launching a new area of research that promises novel insights into endodyogeny. Together, this dissertation presents exciting findings into the composition and function of the T. gondii IMC, with potentially broader impacts for apicomplexan and alveolate cell biology.

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