Abstract
The cystatin family comprises cysteine protease inhibitors distributed in 3 subfamilies (I25A–C). Family members lacking cystatin activity are currently unclassified. Little is known about the evolution of Schistosoma cystatins, their physiological roles, and expression patterns in the parasite life cycle. The present study aimed to identify cystatin homologs in the predicted proteome of three Schistosoma species and other Platyhelminthes. We analyzed the amino acid sequence diversity focused in the identification of protein signatures and to establish evolutionary relationships among Schistosoma and experimentally validated human cystatins. Gene expression patterns were obtained from different developmental stages in Schistosoma mansoni using microarray data. In Schistosoma, only I25A and I25B proteins were identified, reflecting little functional diversification. I25C and unclassified subfamily members were not identified in platyhelminth species here analyzed. The resulting phylogeny placed cystatins in different clades, reflecting their molecular diversity. Our findings suggest that Schistosoma cystatins are very divergent from their human homologs, especially regarding the I25B subfamily. Schistosoma cystatins also differ significantly from other platyhelminth homologs. Finally, transcriptome data publicly available indicated that I25A and I25B genes are constitutively expressed thus could be essential for schistosome life cycle progression. In summary, this study provides insights into the evolution, classification, and functional diversification of cystatins in Schistosoma and other Platyhelminthes, improving our understanding of parasite biology and opening new frontiers in the identification of novel therapeutic targets against helminthiases.
Highlights
Five species of the genus Schistosoma (Trematoda) are involved in the human infection, being the main etiologic agents of human schistosomiasis: Schistosoma mansoni and Schistosoma japonicum causing intestinal schistosomiasis, and Schistosoma haematobium causing urinary schistosomiasis
We evaluated cystatins’ expression in different stages of the parasite life cycle in order to answer the following questions: How many cystatin homologs are present in Schistosoma species and in other Platyhelminthes? Do potential homologs have characteristic sequence features? What are the evolutionary relationships of the cystatin family members in Schistosoma species and their human homologs? Is the transcription of cystatin members during the S. mansoni life cycle stage-specific or is it conserved through the stages assessed?
Such analyses generated an evolutionary view of potential cystatin proteins in three Schistosoma species
Summary
Five species of the genus Schistosoma (Trematoda) are involved in the human infection, being the main etiologic agents of human schistosomiasis: Schistosoma mansoni and Schistosoma japonicum causing intestinal schistosomiasis, and Schistosoma haematobium causing urinary schistosomiasis. According to the World Health Organization, schistosomiasis is endemic in 77 countries, affects more than 200 million people worldwide, and other 779 million live in areas at risk of infection (WHO, 2012). The search for new drug targets based on evolutionary analyses using S. mansoni genomic/proteomic data has been performed (Silva et al, 2011, 2012). Such studies have improved the S. mansoni functional annotation, allowed for a deeper understanding of the genomic complexity and lineage-specific adaptations potentially related to the parasitic lifestyle, and pointed out several proteins as potential drug targets, including proteases
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