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Nuclear hormone receptors in parasitic Platyhelminths.

ABSTRACT: Nuclear receptors (NRs) belong to a large protein superfamily which includes intracellular receptors for secreted hydrophobic signal molecules, such as steroid hormones and thyroid hormones. They regulate development and reproduction in metazoans by binding to the promoter region of their target gene to activate or repress mRNA synthesis. Isolation and characterization of NRs in the parasitic trematode Schistosoma mansoni identified two homologues of mammalian thyroid receptor (TR). This was the first known protostome exhibiting TR homologues. Three novel NRs each possess a novel set of two DNA binding domains (DBD) in tandem with a ligand binding domain (LBD) (2DBD-NRs) isolated in Schistosoma mansoni revealed a novel NR modular structure: A/B-DBD-DBD-hinge-LBD. Full length cDNA of several NRs have been isolated and studied in the parasitic trematodes S. mansoni, S. japonicum and in the cestode Echinococcus multilocularis. The genome of the blood flukes S. mansoni, S. japonicum and S. haematobium, the liver fluke Clonorchis sinensis and the cestode Echinococcus multilocularis have been sequenced. Study of the NR complement in parasitic Platyhelminths will help us to understand the role of NRs in regulation of their development and understand the evolution of NR in animals.

SUBMITTER: Wu W

PROVIDER: S-EPMC6783382 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Nuclear hormone receptors in parasitic Platyhelminths.

Wu Wenjie W LoVerde Philip T PT

Molecular and biochemical parasitology 20190827

Nuclear receptors (NRs) belong to a large protein superfamily which includes intracellular receptors for secreted hydrophobic signal molecules, such as steroid hormones and thyroid hormones. They regulate development and reproduction in metazoans by binding to the promoter region of their target gene to activate or repress mRNA synthesis. Isolation and characterization of NRs in the parasitic trematode Schistosoma mansoni identified two homologues of mammalian thyroid receptor (TR). This was the ...[more]

PMID: 31470045

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Project description:BackgroundThe thioredoxin and/or glutathione pathways occur in all organisms. They provide electrons for deoxyribonucleotide synthesis, function as antioxidant defenses, in detoxification, Fe/S biogenesis and participate in a variety of cellular processes. In contrast to their mammalian hosts, platyhelminth (flatworm) parasites studied so far, lack conventional thioredoxin and glutathione systems. Instead, they possess a linked thioredoxin-glutathione system with the selenocysteine-containing enzyme thioredoxin glutathione reductase (TGR) as the single redox hub that controls the overall redox homeostasis. TGR has been recently validated as a drug target for schistosomiasis and new drug leads targeting TGR have recently been identified for these platyhelminth infections that affect more than 200 million people and for which a single drug is currently available. Little is known regarding the genomic structure of flatworm TGRs, the expression of TGR variants and whether the absence of conventional thioredoxin and glutathione systems is a signature of the entire platyhelminth phylum.ResultsWe examine platyhelminth genomes and transcriptomes and find that all platyhelminth parasites (from classes Cestoda and Trematoda) conform to a biochemical scenario involving, exclusively, a selenium-dependent linked thioredoxin-glutathione system having TGR as a central redox hub. In contrast, the free-living platyhelminth Schmidtea mediterranea (Class Turbellaria) possesses conventional and linked thioredoxin and glutathione systems. We identify TGR variants in Schistosoma spp. derived from a single gene, and demonstrate their expression. We also provide experimental evidence that alternative initiation of transcription and alternative transcript processing contribute to the generation of TGR variants in platyhelminth parasites.ConclusionsOur results indicate that thioredoxin and glutathione pathways differ in parasitic and free-living flatworms and that canonical enzymes were specifically lost in the parasitic lineage. Platyhelminth parasites possess a unique and simplified redox system for diverse essential processes, and thus TGR is an excellent drug target for platyhelminth infections. Inhibition of the central redox wire hub would lead to overall disruption of redox homeostasis and disable DNA synthesis.

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Nuclear hormone receptors in parasitic Platyhelminths.

Publications

Nuclear hormone receptors in parasitic Platyhelminths.

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