Wellcome Centre of Integrative Parasitology, School of Infection and Immunity, University of Glasgow, Glasgow, UK.
X-Ray Sciences Division, Advanced Photon Source, Argonne National Laboratory, Argonne, IL, USA.
Nat Commun. 2023 Jun 20;14(1):3659. doi: 10.1038/s41467-023-39436-y.
Iron is essential to cells as a cofactor in enzymes of respiration and replication, however without correct storage, iron leads to the formation of dangerous oxygen radicals. In yeast and plants, iron is transported into a membrane-bound vacuole by the vacuolar iron transporter (VIT). This transporter is conserved in the apicomplexan family of obligate intracellular parasites, including in Toxoplasma gondii. Here, we assess the role of VIT and iron storage in T. gondii. By deleting VIT, we find a slight growth defect in vitro, and iron hypersensitivity, confirming its essential role in parasite iron detoxification, which can be rescued by scavenging of oxygen radicals. We show VIT expression is regulated by iron at transcript and protein levels, and by altering VIT localization. In the absence of VIT, T. gondii responds by altering expression of iron metabolism genes and by increasing antioxidant protein catalase activity. We also show that iron detoxification has an important role both in parasite survival within macrophages and in virulence in a mouse model. Together, by demonstrating a critical role for VIT during iron detoxification in T. gondii, we reveal the importance of iron storage in the parasite and provide the first insight into the machinery involved.
铁作为呼吸和复制酶的辅因子对细胞至关重要，然而，如果铁的储存不正确，就会导致危险的氧自由基的形成。在酵母和植物中，铁通过液泡铁转运蛋白（VIT）被转运到膜结合的液泡中。这种转运蛋白在包括刚地弓形虫在内的专性细胞内寄生的顶复门寄生虫家族中是保守的。在这里，我们评估了 VIT 和铁储存在刚地弓形虫中的作用。通过删除 VIT，我们发现体外生长略有缺陷和铁超敏性，这证实了它在寄生虫铁解毒中的重要作用，这可以通过清除氧自由基来挽救。我们表明 VIT 的表达受铁在转录和蛋白水平以及通过改变 VIT 定位的调节。在没有 VIT 的情况下，刚地弓形虫通过改变铁代谢基因的表达和增加抗氧化蛋白过氧化氢酶活性来做出反应。我们还表明，铁解毒在寄生虫内巨噬细胞中的存活和在小鼠模型中的毒力中都有重要作用。总之，通过证明 VIT 在刚地弓形虫铁解毒中的关键作用，我们揭示了铁储存对寄生虫的重要性，并首次揭示了涉及的机制。
