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Our previous work reported the role of phosphatidylinositol 4,5-bisphosphates (PIP\n              <jats:sub>2<\/jats:sub>\n              ) signaling in the actin-dependent pathogenicity of\n              <jats:italic>T. vaginalis<\/jats:italic>\n              . This study further demonstrated that iron transiently regulated\n              <jats:italic>T. vaginalis<\/jats:italic>\n              phosphatidylinositol-4-phosphate 5-kinase (\n              <jats:italic>Tv<\/jats:italic>\n              PI4P5K) proteostasis and its complex formation with an active ADP ribosylation factor\n              <jats:italic>Tv<\/jats:italic>\n              Arf220, facilitating co-trafficking to the plasma membrane, crucial for PIP\n              <jats:sub>2<\/jats:sub>\n              production. In dominant-active HA-\n              <jats:italic>Tv<\/jats:italic>\n              Arf220 Q71L mutant,\n              <jats:italic>Tv<\/jats:italic>\n              PI4P5K plasma membrane trafficking, PIP\n              <jats:sub>2<\/jats:sub>\n              production, and intracellular calcium levels were increased, while these processes were inhibited in dominant-negative T31N mutant or those by Brefeldin A (BFA) treatment. Additionally, PIP\n              <jats:sub>2<\/jats:sub>\n              replenishment reversed these inhibitions in the T31N mutant, suggesting the critical role of\n              <jats:italic>Tv<\/jats:italic>\n              Arf220 activation in PIP\n              <jats:sub>2<\/jats:sub>\n              -calcium signaling. Also, T31N mutant and BFA treatment impaired actin dynamics and cytoskeleton-dependent processes in\n              <jats:italic>T. vaginalis<\/jats:italic>\n              , further linking the role of\n              <jats:italic>Tv<\/jats:italic>\n              Arf220 to PIP\n              <jats:sub>2<\/jats:sub>\n              -calcium-dependent actin dynamics. Beyond cytoadherence, during host-parasite interactions,\n              <jats:italic>Tv<\/jats:italic>\n              Arf220 influenced both contact-dependent and -independent cytotoxicity, as well as phagocytotic capacity, contributing to the cytopathogenesis of human vaginal epithelial cells. Our findings underscore the key upstream regulation mechanisms of the PIP\n              <jats:sub>2<\/jats:sub>\n              signaling, orchestrating the interplay between\n              <jats:italic>Tv<\/jats:italic>\n              Arf220-PIP\n              <jats:sub>2<\/jats:sub>\n              -calcium signaling and downstream actin cytoskeleton-driven pathogenicity in\n              <jats:italic>T. vaginalis<\/jats:italic>\n              .\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>\n                <jats:italic>Trichomonas vaginalis<\/jats:italic>\n                actin cytoskeleton-centric pathogenicity is regulated by the phosphatidylinositol 4,5-bisphosphates (PIP\n                <jats:sub>2<\/jats:sub>\n                )-triggered calcium signaling cascade in response to environmental iron, though the detailed mechanism by which iron modulates PIP\n                <jats:sub>2<\/jats:sub>\n                signaling remains unclear. Our findings reveal that iron rapidly induces\n                <jats:italic>T. vaginalis<\/jats:italic>\n                phosphatidylinositol-4-phosphate 5-kinase (\n                <jats:italic>Tv<\/jats:italic>\n                PI4P5K) translation followed by its degradation, while simultaneously activating\n                <jats:italic>Tv<\/jats:italic>\n                Arf220 binding, which facilitates\n                <jats:italic>Tv<\/jats:italic>\n                PI4P5K localization to the plasma membrane for PIP\n                <jats:sub>2<\/jats:sub>\n                production. In contrast to the\n                <jats:italic>Tv<\/jats:italic>\n                Arf220 Q71L mutant, the reduced PIP\n                <jats:sub>2<\/jats:sub>\n                production, intracellular calcium, actin assembly, morphogenesis, and cytoadherence in the dominant-negative T31N mutant were recovered by PIP\n                <jats:sub>2<\/jats:sub>\n                supplementation, indicating the essential role of\n                <jats:italic>Tv<\/jats:italic>\n                Arf220 in PIP\n                <jats:sub>2<\/jats:sub>\n                -dependent calcium signaling. Additionally, the contact-dependent or -independent cytotoxicity, along with the phagocytosis, was impaired in the\n                <jats:italic>Tv<\/jats:italic>\n                PI4P5K- or\n                <jats:italic>Tv<\/jats:italic>\n                Arf220-deficient parasites, as well as in those treated with BAPTA or Latrunculin B. These findings highlight that\n                <jats:italic>Tv<\/jats:italic>\n                Arf220-mediated PIP\n                <jats:sub>2<\/jats:sub>\n                -calcium signaling cascade regulates actin cytoskeleton and cytopathogenicity of\n                <jats:italic>T. vaginalis<\/jats:italic>\n                . This study uncovers a novel pathogenic mechanism and suggests potential therapeutic targets for parasite control.\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/mbio.01864-24","type":"journal-article","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T14:04:17Z","timestamp":1734962657000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Iron triggers\n            <i>Tv<\/i>\n            PI4P5K proteostasis and Arf-mediated cell membrane trafficking to regulate PIP\n            <sub>2<\/sub>\n            signaling crucial for multiple pathogenic activities of the parasitic protozoan\n            <i>Trichomonas vaginalis<\/i>"],"prefix":"10.1128","volume":"16","author":[{"given":"Kuan-Yi","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Tropical Medicine and Parasitology, College of Medicine, National Taiwan University","place":["Taipei, Taiwan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yen-Ju","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Tropical Medicine and Parasitology, College of Medicine, National Taiwan University","place":["Taipei, Taiwan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu-Fan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Tropical Medicine and Parasitology, College of Medicine, National Taiwan University","place":["Taipei, Taiwan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7579-5106","authenticated-orcid":true,"given":"Hong-Ming","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Tropical Medicine and Parasitology, College of Medicine, National Taiwan University","place":["Taipei, Taiwan"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","unstructured":"World Health Organization. 2018. 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