Iron triggers Tv PI4P5K proteostasis and Arf-mediated cell membrane trafficking to regulate PIP 2 signaling crucial for multiple pathogenic activities of the parasitic protozoan Trichomonas vaginalis
Year: 2024
Type: article
Abstract: ABSTRACT Trichomonas vaginalis is the etiologic agent of trichomoniasis, one of the most common non-viral sexually transmitted infections globally. Our previous work reported the role of phosphatidylinositol 4,5-bisphosphates (PIP 2 ) signaling in the actin-dependent pathogenicity of T. vaginalis . This study further demonstrated that iron transiently regulated T. vaginalis phosphatidylinositol-4-phosphate 5-kinase ( Tv PI4P5K) proteostasis and its complex formation with an active ADP ribosylation factor Tv Arf220, facilitating co-trafficking to the plasma membrane, crucial for PIP 2 production. In dominant-active HA- Tv Arf220 Q71L mutant, Tv PI4P5K plasma membrane trafficking, PIP 2 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 2 replenishment reversed these inhibitions in the T31N mutant, suggesting the critical role of Tv Arf220 activation in PIP 2 -calcium signaling. Also, T31N mutant and BFA treatment impaired actin dynamics and cytoskeleton-dependent processes in T. vaginalis , further linking the role of Tv Arf220 to PIP 2 -calcium-dependent actin dynamics. Beyond cytoadherence, during host-parasite interactions, Tv 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 2 signaling, orchestrating the interplay between Tv Arf220-PIP 2 -calcium signaling and downstream actin cytoskeleton-driven pathogenicity in T. vaginalis . IMPORTANCE Trichomonas vaginalis actin cytoskeleton-centric pathogenicity is regulated by the phosphatidylinositol 4,5-bisphosphates (PIP 2 )-triggered calcium signaling cascade in response to environmental iron, though the detailed mechanism by which iron modulates PIP 2 signaling remains unclear. Our findings reveal that iron rapidly induces T. vaginalis phosphatidylinositol-4-phosphate 5-kinase ( Tv PI4P5K) translation followed by its degradation, while simultaneously activating Tv Arf220 binding, which facilitates Tv PI4P5K localization to the plasma membrane for PIP 2 production. In contrast to the Tv Arf220 Q71L mutant, the reduced PIP 2 production, intracellular calcium, actin assembly, morphogenesis, and cytoadherence in the dominant-negative T31N mutant were recovered by PIP 2 supplementation, indicating the essential role of Tv Arf220 in PIP 2 -dependent calcium signaling. Additionally, the contact-dependent or -independent cytotoxicity, along with the phagocytosis, was impaired in the Tv PI4P5K- or Tv Arf220-deficient parasites, as well as in those treated with BAPTA or Latrunculin B. These findings highlight that Tv Arf220-mediated PIP 2 -calcium signaling cascade regulates actin cytoskeleton and cytopathogenicity of T. vaginalis . This study uncovers a novel pathogenic mechanism and suggests potential therapeutic targets for parasite control.
Source: mBio
Authors: Kuan-Yi Wu, Yen-Ju Chen, Shu-Fan Lin, Hong-Ming Hsu
Institution: National Taiwan University
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,900
OpenAlex ID: W4405703368