A novel component of the cytosolic iron-sulfur biogenesis pathway, TgHCF101, as a potential drug target in Toxoplasma gondii

Toxoplasma gondii is a unicellular eukaryotic parasite responsible for causing toxoplasmosis in Humans. The disease, asymptomatic in most instances, can be threatening to immunocompromised individuals. The parasite infects about a third of the global population, mainly through undercooked meat consumption, utilizing cysts as a form of persistence. T. gondii, as an obligate intracellular pathogen, scavenges essential nutrients, including iron, crucial to its growth, from its host cell. Both the host and the parasite are using iron; as it is a component of protein cofactors like heme or iron-sulfur (Fe-S) clusters, vital to the parasite. Fe-S clusters represent ancient and indispensable molecular structures formed by specific arrangements of coordinated iron and sulfur atoms. Their biogenesis and specific insertion into target proteins rely on multiprotein complexes fairly conserved across species. Proteins containing Fe-S clusters play crucial roles in cellular functions such as genome maintenance, protein translation, energy conversion and various enzymatic activities implying electron transfer mechanisms. Within T. gondii, three metabolic pathways for Fe-S clusters biogenesis co-exist, located within the mitochondrion, in the plastid of the parasite, or in the cytoplasm. We have characterized the T. gondii homologue of a protein called HCF101, absent from mammals but playing a role in transferring Fe-S clusters to client proteins in the chloroplasts of land plants. Our findings demonstrate that TgHCF101 is essential for parasite viability. However, in contrast to plants, we have shown that it is not associated with any plastid-related function in T. gondii; instead, it is part of the CIA (Cytosolic Iron-Sulfur cluster Assembly) pathway. Even in pan-eukaryotic pathways like the CIA pathway, the involvement of an essential lineage-specific protein like TgHCF101 provides the perspective of discovering parasite-specific features that may be exploited for therapeutic intervention.