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bioRxiv · 10.1101/2025.05.15.654346

A Protein Disulfide Isomerase Coordinates Redox Homeostasis and ER Calcium Regulation for Optimal Lytic Cycle Progression in Toxoplasma gondii

Moen, K. E.·Moreno, S. N. J.
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Abstract

The endoplasmic reticulum (ER) maintains an oxidative environment that facilitates disulfide bond formation, a critical process for proper protein folding. Protein disulfide isomerases (PDIs) are ER resident enzymes that facilitate the formation, breakage, and rearrangement of disulfide bonds between cysteine residues, thereby stabilizing protein structures. Although PDIs are functionally diverse, they all contain at least 1 thioredoxin-like domain and mediate disulfide exchange through their conserved CXXC motifs. The Apicomplexan parasite, Toxoplasma gondii, infects approximately one third of the world population, posing a significant risk to immunosuppressed individuals and unborn fetuses. The fast-replicating tachyzoite form engages in a lytic cycle, causing host tissue damage and contributing to pathogenesis. While approximately 26 PDIs are predicted to be present in T. gondii, their specific roles remain largely unexplored. In this study, we investigate TgPDIA3, a T. gondii PDI localized to the ER, along with several of its interacting protein substrates. We explore its role in ER redox activity and calcium sequestration and assess how these functions contribute to the parasites lytic cycle. ImportanceThe lytic cycle of Toxoplasma gondii is essential to the pathogenesis of toxoplasmosis, with calcium signaling playing a crucial role in driving this process. Cytosolic calcium is tightly regulated through either sequestration into intracellular stores or extrusion from the cell. The ER, likely the largest calcium store in T. gondii, remains poorly characterized. In this study, we identify a link between ER redox regulation and calcium homeostasis and signaling in T. gondii. These findings suggest that redox-controlled calcium homeostasis and flux in the ER is a key driver of the parasites lytic cycle progression.

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Moen, K. E., Moreno, S. N. J.. 2025-05-15. A Protein Disulfide Isomerase Coordinates Redox Homeostasis and ER Calcium Regulation for Optimal Lytic Cycle Progression in Toxoplasma gondii. https://doi.org/10.1101/2025.05.15.654346

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