Schistosoma mansoni TGF-β Receptor II: Role in Host Ligand-Induced Regulation of a Schistosome Target Gene

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Abstract
Members of transforming growth factor-beta (TGF-β) superfamily play pivotal roles in development in multicellular organisms. We report the functional characterization of the Schistosoma mansoni type II receptor (SmTβRII). Mining of the S. mansoni expressed sequence tag (EST) database identified an EST clone that shows homology to the kinase domain of type II receptors from different species. The amplified EST sequence was used as a probe to isolate a cDNA clone spanning the entire coding region of a type II serine/threonine kinase receptor. The interaction of SmTβRII with SmTβRI was elucidated and shown to be dependent on TGF-β ligand binding. Furthermore, in the presence of human TGF-β1, SmTβRII was able to activate SmTβRI, which in turn activated SmSmad2 and promoted its interaction with SmSmad4, proving the transfer of the signal from the receptor complex to the Smad proteins. Gynaecophoral canal protein (GCP), whose expression in male worms is limited to the gynaecophoric canal, was identified as a potential TGF-β target gene in schistosomes. Knocking down the expression of SmTβRII using short interfering RNA molecules (siRNA) resulted in a concomitant reduction in the expression of GCP. These data provide evidence for the direct involvement of SmTβRII in mediating TGF-β–induced activation of the TGF-β target gene, SmGCP, within schistosome parasites. The results also provide additional evidence for a role for the TGF-β signaling pathway in male-induced female reproductive development. Schistosomes are multicellular parasites that infect 200 million people worldwide. Schistosome development in the human host likely involves host molecules that regulate biological processes of the parasite. Members of transforming growth factor-beta (TGF-β) superfamily play pivotal roles in development in multicellular organisms. TGF-β signaling requires ligand binding to a specific surface receptor, TGF-β type II receptor. The authors isolated the schistosome TGF-β type II receptor (SmTβRII), which was found to be biologically active and responded to stimulation by host TGF-β. The gynaecophoric canal is a ventral groove in the male worm in which the female must reside for sexual maturity. Gynaecophoral canal protein (GCP) is a protein whose expression in male worms is limited to the gynaecophoric canal and is implicated in female reproductive maturation. GCP expression was found to be regulated by human TGF-β. Knocking down the expression of SmTβRII resulted in a concomitant reduction in the expression of GCP, providing evidence for the direct involvement of SmTβRII-mediated, host TGF-β–induced regulation of schistosome gene expression. This study implicates the TGF-β signaling pathway in worm pairing, a prerequisite for female egg production. Because the eggs produced by the worm pairs are responsible for pathogenesis, the authors' research identifies potential targets for intervention.