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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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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&lt;0.05; α-NAGAL &gt; 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 (&gt;90%) of smp_089290 in adult worms significantly inhibited α-NAGAL activity when compared to control worms (siLuc treated males, p&lt;0.01; siLuc treated females, p&lt;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.</abstract><type>Journal Article</type><journal>PLOS Pathogens</journal><volume>18</volume><journalNumber>1</journalNumber><paginationStart>e1009828</paginationStart><paginationEnd/><publisher>Public Library of Science (PLoS)</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>1553-7374</issnElectronic><keywords>Schistosoma mansoni, SmNAGAL, glycosyl hydrolases, schistosome parasites</keywords><publishedDay>13</publishedDay><publishedMonth>1</publishedMonth><publishedYear>2022</publishedYear><publishedDate>2022-01-13</publishedDate><doi>10.1371/journal.ppat.1009828</doi><url>http://dx.doi.org/10.1371/journal.ppat.1009828</url><notes/><college>COLLEGE NANME</college><department>Pharmacy</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>PHAR</DepartmentCode><institution>Swansea University</institution><apcterm/><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. 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spelling v2 64431 2023-09-05 Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production 7e5526209f02734f57ba19b0d17604ec 0000-0001-8580-1293 Gilda Padalino Gilda Padalino true false 2023-09-05 PHAR 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. Journal Article PLOS Pathogens 18 1 e1009828 Public Library of Science (PLoS) 1553-7374 Schistosoma mansoni, SmNAGAL, glycosyl hydrolases, schistosome parasites 13 1 2022 2022-01-13 10.1371/journal.ppat.1009828 http://dx.doi.org/10.1371/journal.ppat.1009828 COLLEGE NANME Pharmacy COLLEGE CODE PHAR Swansea University 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. 2024-01-08T14:12:02.4677152 2023-09-05T16:08:07.8672251 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Pharmacy Benjamin J. Hulme 0000-0002-5638-6323 1 Kathrin K. Geyer 0000-0001-7537-8663 2 Josephine E. Forde-Thomas 3 Gilda Padalino 0000-0001-8580-1293 4 Dylan W. Phillips 0000-0002-9139-5727 5 Wannaporn Ittiprasert 0000-0001-9411-8883 6 Shannon E. Karinshak 0000-0002-2079-0973 7 Victoria H. Mann 8 Iain W. Chalmers 0000-0001-8674-1181 9 Paul J. Brindley 0000-0003-1765-0002 10 Cornelis H. Hokke 0000-0003-3545-7804 11 Karl F. Hoffmann 0000-0002-3932-5502 12 64431__28749__136fa327b3df4fd7854d75cf0f6fa647.pdf 64431.VOR.pdf 2023-10-10T10:22:50.5143064 Output 4086209 application/pdf Version of Record true © 2022 Hulme et al. Distributed under the terms of a Creative Commons Attribution 4.0 License (CC BY 4.0). true eng https://creativecommons.org/licenses/by/4.0/
title Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production
spellingShingle Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production
Gilda Padalino
title_short Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production
title_full Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production
title_fullStr Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production
title_full_unstemmed Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production
title_sort Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production
author_id_str_mv 7e5526209f02734f57ba19b0d17604ec
author_id_fullname_str_mv 7e5526209f02734f57ba19b0d17604ec_***_Gilda Padalino
author Gilda Padalino
author2 Benjamin J. Hulme
Kathrin K. Geyer
Josephine E. Forde-Thomas
Gilda Padalino
Dylan W. Phillips
Wannaporn Ittiprasert
Shannon E. Karinshak
Victoria H. Mann
Iain W. Chalmers
Paul J. Brindley
Cornelis H. Hokke
Karl F. Hoffmann
format Journal article
container_title PLOS Pathogens
container_volume 18
container_issue 1
container_start_page e1009828
publishDate 2022
institution Swansea University
issn 1553-7374
doi_str_mv 10.1371/journal.ppat.1009828
publisher Public Library of Science (PLoS)
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Pharmacy{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Pharmacy
url http://dx.doi.org/10.1371/journal.ppat.1009828
document_store_str 1
active_str 0
description 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.
published_date 2022-01-13T14:12:03Z
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