Protein disulfide isomerase PDI8 is indispensable for parasite growth and associated with secretory protein processing in <i>Toxoplasma gondii</i>

Apicomplexans, a phylum of intracellular parasites, encompass various zoonotic pathogens, including <i>Plasmodium</i>, <i>Cryptosporidium</i>, <i>Toxoplasma</i>, and <i>Babesia</i>, causing a significant economic burden on human populations. These parasites exhibit hypersensitivity to disruptions in endoplasmic reticulum (ER) redox homeostasis, necessitating the presence of ER-localized thioredoxin (Trx) superfamily proteins, particularly protein disulfide isomerase (PDI), for proper oxidative folding. However, the functional characteristics of ER-localized PDI proteins in <i>Toxoplasma gondii</i> remain largely unexplored. In this study, we identified two ER-localized proteins, namely, TgPDI8 and TgPDI6, and demonstrated the indispensable role of TgPDI8 in parasite survival. Through a comprehensive multi-omics analysis, we elucidated the crucial role of TgPDI8 in the processing of secretory proteins in <i>T. gondii</i>. Additionally, we introduced a novel ER-anchored TurboID method to label and identify canonical secretory proteins in <i>T. gondii</i>. This research opens up new avenues for understanding oxidative folding and the secretory pathway in apicomplexan parasites, laying the groundwork for future advancements in antiparasitic drug development.