Schistosoma japonicum: Immunoinhibitory Studies on Hemoglobin Digestion Using Heterologous Antiserum to Bovine Cathepsin D

Bogitsh, Burton J.; Kirschner, Kenneth F.; Rotmans, J. P.

doi:10.2307/3283643

Cited by 26 publications

(19 citation statements)

References 15 publications

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“…However, there was significant degradation of albumin (20 -40%) at pH 6 -6.5. Bogitsh et al (18,46) localized cathepsin D to autophagic vacuoles in the gastrodermis, suggesting that the primary site of action of cathepsin D is the gastrodermal lysosome/endosome. It has been shown that S. mansoni cathepsin D cannot degrade hemoglobin at the estimated pH of the gut lumen (pH 6.0 -6.4) (15,52).…”

Section: Discussionmentioning

confidence: 99%

“…2 Furthermore, RNAi knockdown of SmCB1 alone in schistosomula, the early developmental stage in the mammalian bloodstream, produced a significant arrest of worm development (54). Finally, antiserum to bovine cathepsin D or pepstatin treatment has been shown to inhibit protein digestion in schistosomula fed red blood cells (18). In malaria parasites, where a remarkably similar network of both cysteine and aspartic proteases functions to degrade hemoglobin, treatment of parasite cultures with a combination of cysteine and aspartic protease inhibitors is synergistic (55).…”

Section: Discussionmentioning

confidence: 99%

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A Multienzyme Network Functions in Intestinal Protein Digestion by a Platyhelminth Parasite

Delcroix

Sajid

Caffrey

et al. 2006

Journal of Biological Chemistry

212

205

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Proteases frequently function not only as individual enzymes but also in cascades or networks. A notable evolutionary switch occurred in one such protease network that is involved in protein digestion in the intestine. In vertebrates, this is largely the work of trypsin family serine proteases, whereas in invertebrates, cysteine proteases of the papain family and aspartic proteases assume the role. Utilizing a combination of protease class-specific inhibitors and RNA interference, we deconvoluted such a network of major endopeptidases functioning in invertebrate intestinal protein digestion, using the parasitic helminth, Schistosoma mansoni as an experimental model. We show that initial degradation of host blood proteins is ordered, occasionally redundant, and substrate-specific. Although inhibition of parasite cathepsin D had a greater effect on primary cleavage of hemoglobin, inhibition of cathepsin B predominated in albumin degradation. Nevertheless, in both cases, inhibitor combinations were synergistic. An asparaginyl endopeptidase (legumain) also synergized with cathepsin B and L in protein digestion, either by zymogen activation or facilitating substrate cleavage. This protease network operates optimally in acidic pH compartments either in the gut lumen or in vacuoles of the intestinal lining cells. Defining the role of each of these major enzymes now provides a clearer understanding of the function of a complex protease network that is conserved throughout invertebrate evolution. It also provides insights into which of these proteases are logical targets for development of chemotherapy for schistosomiasis, a major global health problem.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Multienzyme Network Functions in Intestinal Protein Digestion by a Platyhelminth Parasite

Delcroix

Sajid

Caffrey

et al. 2006

Journal of Biological Chemistry

212

205

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“…Bogitsh et al (19) reported hemoglobinase activity in extracts of S. japonicum that was inhibited by pepstatin but was unaffected by leupeptin, an inhibitor of cysteine proteinases. In contrast, Chappell and Dresden (20) attributed the hemoglobinase activity in schistosome ES to a cysteine proteinase since it was inhibited by leupeptin.…”

Section: Aspartic Proteinase Gene Identified In the Genomes Of S Japmentioning

confidence: 99%

Cloning and Characterization of the Schistosoma japonicum Aspartic Proteinase Involved in Hemoglobin Degradation

Becker

Harrop

Dalton

et al. 1995

Journal of Biological Chemistry

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A cDNA encoding a Schistosoma japonicum aspartic proteinase was cloned, sequenced, and found to encode a zymogen of 380 amino acid residues, and its gene was shown to be present as a single copy in the S. japonicum genome. Identity comparisons showed that the enzyme (Sjpasp) was most closely related to the cathepsin Ds. The deduced amino acid sequence has four potential glycosylation sites, two of which are in identical positions to the two glycosylation sites of human kidney lysosomal cathepsin D. Furthermore, all four disulfide bonds found in mammalian cathepsin D sequences are present in Sjpasp, although the ␤-hairpin (loop 3), which is cleaved during maturation of vertebrate cathepsin Ds to yield light and heavy chain subunits, is absent from Sjpasp. While most residues involved in substrate specificity and catalysis of aspartic proteinases are preserved in Sjpasp, several residues in these regions exhibit changes that may result in a novel substrate specificity. Aspartic proteinase activity is present in extracts of adult S. japonicum and Schistosoma mansoni and in culture media in which schistosomes were maintained and was capable of digesting hemoglobin. The schistosome aspartic proteinase may play a pivotal role in the catabolism of hemoglobin obtained from host erythrocytes.

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“…Identifying the key enzymes that facilitate host nutrient degradation is important not only to understand the biology and pathogenesis of schistosome infection but also to identify those enzymes that might be viable targets for development of new interventions. Cysteine and aspartic proteases have been described in secretions and/or worm extracts of schistosomules and adult worms [2], and previous studies have shown that inhibitors of either cysteine proteases [3] or aspartic proteases [4] block hemoglobin degradation and arrest schistosome development and egg production. A proteolytic cascade or network involving aspartic and cysteine proteases has been proposed as catalyzing hemoglobin degradation in schistosomes [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

RNA interference of Schistosoma mansoni cathepsin D, the apical enzyme of the hemoglobin proteolysis cascade

Morales

Rinaldi

Gobert

et al. 2008

Molecular and Biochemical Parasitology

117

111

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The aspartic protease cathepsin D (Clan AA, Family A1) is expressed in the schistosome gut where it plays an apical role in the digestion of hemoglobin released from ingested erythrocytes. In this report, RNA interference approaches were employed to investigate the effects of knockdown of schistosome cathepsin D. Cultured schistosomules of Schistosoma mansoni were exposed by square wave electroporation to double stranded RNA (dsRNA) specific for cDNA encoding S. mansoni cathepsin D. RNAi mediated reductions in transcript levels led to phenotypic changes including significant growth retardation in vitro and suppression of aspartic protease enzyme activity. In addition, black-pigmented heme, the end point by-product of normal hemoglobin proteolysis that accumulates in the schistosome gut, was not apparent within the guts of the treated schistosomules. Rather, their guts appeared to be red in color, rather than black, apparently indicating the presence of intact rather than digested host hemoglobin. These phenotypic effects were apparent when either of two forms of dsRNA, a long form spanning the entire target transcript or a short form specific for the 3'-region were employed. Off-target effects were not apparent in transcript levels of the gut-localized cysteine protease cathepsin B1. Finally, cathepsin D may be an essential enzyme in the mammal-parasitic stages of schistosomes because schistosomules treated ex vivo with dsRNA did not survive to maturity after transfer into Balb/c mice. These and earlier findings suggest that, given its essential function in parasite nutrition, schistosome cathepsin D could be developed as a target for novel anti-schistosomal interventions.

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Schistosoma japonicum: Immunoinhibitory Studies on Hemoglobin Digestion Using Heterologous Antiserum to Bovine Cathepsin D

Cited by 26 publications

References 15 publications

A Multienzyme Network Functions in Intestinal Protein Digestion by a Platyhelminth Parasite

A Multienzyme Network Functions in Intestinal Protein Digestion by a Platyhelminth Parasite

Cloning and Characterization of the Schistosoma japonicum Aspartic Proteinase Involved in Hemoglobin Degradation

RNA interference of Schistosoma mansoni cathepsin D, the apical enzyme of the hemoglobin proteolysis cascade

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