Abstract
The Venus Kinase Receptor (VKR) is a single transmembrane molecule composed of an intracellular tyrosine kinase domain close to that of insulin receptor and an extracellular Venus Flytrap (VFT) structure similar to the ligand binding domain of many class C G Protein Coupled Receptors. This receptor tyrosine kinase (RTK) was first discovered in the platyhelminth parasite Schistosoma mansoni, then in a large variety of invertebrates. A single vkr gene is found in most genomes, except in S. mansoni in which two genes Smvkr1 and Smvkr2 exist. VKRs form a unique family of RTKs present only in invertebrates and their biological functions are still to be discovered. In this work, we show that SmVKRs are expressed in the reproductive organs of S. mansoni, particularly in the ovaries of female worms. By transcriptional analyses evidence was obtained that both SmVKRs fulfill different roles during oocyte maturation. Suppression of Smvkr expression by RNA interference induced spectacular morphological changes in female worms with a strong disorganization of the ovary, which was dominated by the presence of primary oocytes, and a defect of egg formation. Following expression in Xenopus oocytes, SmVKR1 and SmVKR2 receptors were shown to be activated by distinct ligands which are L-Arginine and calcium ions, respectively. Signalling analysis in Xenopus oocytes revealed the capacity of SmVKRs to activate the PI3K/Akt/p70S6K and Erk MAPK pathways involved in cellular growth and proliferation. Additionally, SmVKR1 induced phosphorylation of JNK (c-Jun N-terminal kinase). Activation of JNK by SmVKR1 was supported by the results of yeast two-hybrid experiments identifying several components of the JNK pathway as specific interacting partners of SmVKR1. In conclusion, these results demonstrate the functions of SmVKR in gametogenesis, and particularly in oogenesis and egg formation. By eliciting signalling pathways potentially involved in oocyte proliferation, growth and migration, these receptors control parasite reproduction and can therefore be considered as potential targets for anti-schistosome therapies.
Highlights
Trematode parasites of the Schistosoma genus are responsible for schistosomiasis or bilharzia, one of the most important parasitic endemias worldwide in terms of mortality and morbidity
We investigated the importance of Venus Kinase Receptors (VKRs) which are unusual receptor tyrosine kinases (RTKs) with an extracellular Venus Flytrap (VFT) ligand-binding domain in the control of reproduction of schistosomes
SmVKRs are expressed in female ovaries of Schistosoma mansoni and the knockdown of their expression provoked dramatic alterations of the oocyte content in ovaries and reduction of egg formation
Summary
Trematode parasites of the Schistosoma genus are responsible for schistosomiasis or bilharzia, one of the most important parasitic endemias worldwide in terms of mortality and morbidity. According to the World Health Organisation, more than 240 million people are currently infected by schistosomes, with about 200 000 deaths per year [1]. The pathology of schistosomiasis mostly results from the accumulation of parasite eggs in host tissues. Among the several hundreds of eggs laid daily by each female schistosome, a large part gets trapped into host tissues and elicits immune responses, such as inflammation and granuloma formation, causing severe disorders, hepatosplenomegaly, hepatic fibrosis and bladder cancer [2]. Praziquantel (PZQ) is the only drug currently used to cure schistosomiasis. This drug is active against the three main species infecting humans (S. mansoni, S. haematobium, S. japonicum). Its widespread use for mass treatment since the early 80’s, has already led to the emergence/of drug-insensitive
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