Tyrosine kinase 4 is involved in the reproduction of the platyhelminth parasite Schistosoma japonicum

Abstract

BackgroundSchistosomiasis is one of the most common parasitic diseases affecting millions of humans and animals worldwide. Understanding the signal transduction pathways and the molecular basis of reproductive regulation in schistosomes is critically important for developing new strategies for preventing and treating these infections. Syk kinases regulate the proliferation, differentiation, morphogenesis, and survival of various types of cells and have been identified in invertebrates. Tyrosine kinase 4 (TK4), a member of the Syk kinase family, plays a pivotal role in gametogenesis in S. mansoni, affecting the development of the testis and ovaries in this parasite. The role of TK4, however, in the reproduction of S. japonicum is poorly understood. MethodsHere, the complete coding sequence of TK4 gene in S. japonicum (SjTK4) was cloned and characterized. The expression of SjTK4 was analyzed at different life-cycle stages and in various tissues of S. japonicum by qPCR. Piceatannol, a Syk kinase inhibitor, was applied to S. japonicum in vitro. The piceatannol-induced morphological changes of the parasites were observed using confocal laser scanning microscopy and the alterations in important egg-shell synthesis-related genes were examined using qPCR analyses.Results SjTK4 mRNA was differentially expressed throughout the life-cycle of S. japonicum. SjTK4 mRNA was highly expressed in the ovary and testis of S. japonicum, with the level of gene expression significantly higher in males than in females. The expression levels of some important egg-shell synthesis related genes were higher in the piceatannol-treated groups than in the vehicle-treated control group and the number of eggs and germ cells also decreased in a concentration-dependent manner. Importantly, large pore-like structures can be found in the testis and ovaries of males and females after treating with piceatannol.ConclusionThe results suggest that SjTK4 may play an important role in regulating gametogenesis of S. japonicum. The findings may help better understand the fundamental biology of S. japonicum. Moreover, the effect of S. japonicum treatment by piceatannol provides us with a new idea that inhibition of SjTK4 signaling pathway can effectively retard the development of the testis and ovaries.

Prohibitin 1 (PHB1) controls growth and development and regulates proliferation and apoptosis in Schistosoma japonicum

“…So, our results revealed that SjPhb1 is essential for the growth and development of schistosomes. It was reported that PHB is important in embryonic development and is required for the differentiation of somatic and germline cells in the larval gonads of C elegans , highlighting its essential role in regulating fat metabolism and mitochondrial proliferation during aging 27,28,37,57 . The growth and development of schistosomes depends on continuous nutrient acquisition and metabolism from the host environment, 58 and vitellaria is a highly proliferative organ that occupies almost two thirds of the posterior female worm body and contains a lot of lipid droplets in the vitelline cells, 52,59,60 which implied that Sj PHB1 may also perform similar functions in S. japonicum as PHB does in C elegans .…”

“…We also observed that the digested blood products in the intestine of SjPhb1 knockdown female worms were much less than those in the intestine of control female worms with light black or gray in color of the intestine of SjPhb1 knockdown female worms vs dark black in color of the intestine of control female worms ( Figure S3), which suggested potential defects in feeding or utilizing host blood in the SjPhb1 knockdown female worms, and this is also a probable cause for their retarded growth and development during aging. 27,28,37,57 The growth and development of schistosomes depends on continuous nutrient acquisition and metabolism from the host environment, 58 and vitellaria is a highly proliferative organ that occupies almost two thirds of the posterior female worm body and contains a lot of lipid droplets in the vitelline cells, 52,59,60 which implied that SjPHB1 may also perform similar functions in S. japonicum as PHB does in C elegans.…”

Protein Kinases: Potential Drug Targets Against Schistosoma japonicum

“…Later, it was discovered that the SjTK4 amino acid sequence shows 76.9% identity and 82.7% similarity with SmTK4 sequence, the gene is differentially expressed in all developmental stages of schistosome both in females and males. With the therapy of piceatannol (a Syk kinase-specific inhibitor), many morphological changes were observed in the testes and ovaries of S. japonicum , and the size and number of whole germ cells in both the testis and ovary are smaller and fewer than the control group, suggesting that TK4 may have a significant effect on the production and development of eggs in vitro ( Ding et al., 2017 ). In addition, the application of piceatannol significantly upregulates the expression of genes related to egg-shell production including P14, P48, egg-shell precursor, and FS800, which in agreement with the results in imatinib-treated S. mansoni , further indicating the functional similarity between SjTK4 and SmTK4 ( Buro et al., 2014 ).…”

Global phosphoproteome analysis reveals significant differences between sporulated oocysts of virulent and avirulent strains of Toxoplasma gondii

“…Syk kinases, identi ed in invertebrates, regulate the proliferation, differentiation, and survival of various types of cells. Among Syk kinase family, tyrosine kinase 4 (TK4) is a kinase expressed in Schistosoma mansoni and S. japonicum, which plays a pivotal role in the development of the testis and ovaries in S. mansoni and regulates the gametogenesis of S. japonicum [40]. The fact that Src inhibitors can affect the actin cytoskeleton of Entamoeba histolytica and inhibit the entry of Trypanosoma cruzi provides new targets for designing new drugs against protozoa [41][42].…”