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Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production

Benjamin J. Hulme Orcid Logo, Kathrin K. Geyer Orcid Logo, Josephine E. Forde-Thomas, Gilda Padalino Orcid Logo, Dylan W. Phillips Orcid Logo, Wannaporn Ittiprasert Orcid Logo, Shannon E. Karinshak Orcid Logo, Victoria H. Mann, Iain W. Chalmers Orcid Logo, Paul J. Brindley Orcid Logo, Cornelis H. Hokke Orcid Logo, Karl F. Hoffmann Orcid Logo

PLOS Pathogens, Volume: 18, Issue: 1, Start page: e1009828

Swansea University Author: Gilda Padalino Orcid Logo

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DOI (Published version): 10.1371/journal.ppat.1009828

Abstract

α-galactosidase (α-GAL) and α-N-acetylgalactosaminidase (α-NAGAL) are two glycosyl hydrolases responsible for maintaining cellular homeostasis by regulating glycan substrates on proteins and lipids. Mutations in the human genes encoding either enzyme lead to neurological and neuromuscular impairment...

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Published in: PLOS Pathogens
ISSN: 1553-7374
Published: Public Library of Science (PLoS) 2022
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URI: https://cronfa.swan.ac.uk/Record/cronfa64431
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Abstract: α-galactosidase (α-GAL) and α-N-acetylgalactosaminidase (α-NAGAL) are two glycosyl hydrolases responsible for maintaining cellular homeostasis by regulating glycan substrates on proteins and lipids. Mutations in the human genes encoding either enzyme lead to neurological and neuromuscular impairments seen in both Fabry- and Schindler/Kanzaki- diseases. Here, we investigate whether the parasitic blood fluke Schistosoma mansoni, responsible for the neglected tropical disease schistosomiasis, also contains functionally important α-GAL and α-NAGAL proteins. As infection, parasite maturation and host interactions are all governed by carefully-regulated glycosylation processes, inhibiting S. mansoni’s α-GAL and α-NAGAL activities could lead to the development of novel chemotherapeutics. Sequence and phylogenetic analyses of putative α-GAL/α-NAGAL protein types showed Smp_089290 to be the only S. mansoni protein to contain the functional amino acid residues necessary for α-GAL/α-NAGAL substrate cleavage. Both α-GAL and α-NAGAL enzymatic activities were higher in females compared to males (p<0.05; α-NAGAL > α-GAL), which was consistent with smp_089290’s female biased expression. Spatial localisation of smp_089290 revealed accumulation in parenchymal cells, neuronal cells, and the vitellaria and mature vitellocytes of the adult schistosome. siRNA-mediated knockdown (>90%) of smp_089290 in adult worms significantly inhibited α-NAGAL activity when compared to control worms (siLuc treated males, p<0.01; siLuc treated females, p<0.05). No significant reductions in α-GAL activities were observed in the same extracts. Despite this, decreases in α-NAGAL activities correlated with a significant inhibition in adult worm motility as well as in egg production. Programmed CRISPR/Cas9 editing of smp_089290 in adult worms confirmed the egg reduction phenotype. Based on these results, Smp_089290 was determined to act predominantly as an α-NAGAL (hereafter termed SmNAGAL) in schistosome parasites where it participates in coordinating movement and oviposition processes. Further characterisation of SmNAGAL and other functionally important glycosyl hydrolases may lead to the development of a novel anthelmintic class of compounds.
Keywords: Schistosoma mansoni, SmNAGAL, glycosyl hydrolases, schistosome parasites
College: Faculty of Medicine, Health and Life Sciences
Funders: This research was funded in whole, or in part, by the Wellcome Trust (Grant number 107475/Z/15/Z) to KFH. At George Washington University Medical School, schistosome-infected mice and snails were provided by the NIAID Schistosomiasis Resource Center of the Biomedical Research Institute, Rockville, Maryland through NIH-NIAID Contract HHSN272201000005I for distribution through BEI Resources. BJH was supported from a kind donation provided by David & Eleanor James.
Issue: 1
Start Page: e1009828

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