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PreprintCited by 0Toxoplasma gondii Research StudiesEndoplasmic Reticulum Stress and DiseaseRedox biology and oxidative stress

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

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Moen, Katherine E, Moreno, Silvia N J·2025·mBio
DOI 10.1101/2025.05.15.654346PMC PMC12132493

Preprint — published as 10.1128/mbio.03124-25 · Paper page

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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 parasite’s lytic cycle. Importance: The 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 parasite’s lytic cycle progression.

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Metadata

Authors
Moen, K. E., & Moreno, S. N. J.
Affiliations
University of Georgia (US)
Corresponding author
Moreno, Silvia N J
ORCID
Moreno, Silvia N J
Venue
mBio
Publisher
openRxiv
Published
2025-05-15
Volume
17
Issue
5
Pages
e0312425-e0312425
ISSN
2150-7511 (ISSN-L)
DOI
10.1101/2025.05.15.654346
PMC
PMC12132493
OpenAlex
W7147608578
Cited by
0
References
2
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • mBio (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed Central (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • University of Nebraska-Lincoln
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases (T32AI060546, R21AI154931, R01AI174600)
Topics
  • Life Sciences › Immunology and Microbiology › Parasitology › Toxoplasma gondii Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
Toxoplasma gondii, protein disulfide isomerase, endoplasmic reticulum, redox homeostasis, calcium signaling, lytic cycle, tachyzoites, disulfide bond formation, thioredoxin-like domain, CXXC motif, parasite invasion, parasite virulence, Apicomplexa

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