Why Do Intravascular Schistosomes Coat Themselves in Glycolytic Enzymes?

Pirovich, David; Da’dara, Akram A.; Skelly, Patrick J.

doi:10.1002/bies.201900103

Cited by 13 publications

(13 citation statements)

References 77 publications

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“…While glycolysis is a conserved biochemical pathway that takes place in the cytosol of cells, several enzymes that drive this pathway have been reported to be present at the schistosome surface following proteomic analysis (reviewed by Pirovich et al, 2019). The glycolytic enzymes enolase and GAPDH were both identified as schistosome surface proteins in ten of 11 independent schistosome tegumental proteomic studies (Pirovich et al, 2019). No other glycolytic enzymes were found more frequently in the schistosome tegumentome.…”

Section: Discussionmentioning

confidence: 99%

“…Is there any selective advantage for the parasites to express the protein in this location? In schistosomes, and in other systems, evidence is accumulating that extracellular glycolytic enzymes like GAPDH can be engaged in non-traditional, nonglycolytic or 'moonlighting' functions relating, for example, to immune modulation and/or blood clot dissolution (Karkowska-Kuleta and Kozik, 2014;Pirovich et al, 2019;Sirover, 2017). We previously showed that live intravascular schistosomes could promote PLMG activation in the presence of tPA (Figueiredo et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

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Schistosoma mansoniglyceraldehyde-3-phosphate dehydrogenase enhances formation of the blood-clot lysis protein plasmin

2020

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Schistosomes are intravascular blood flukes that cause the parasitic disease schistosomiasis. In agreement with Schistosoma mansoni (Sm) proteomic analysis, we show here that the normally intracellular glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is also found at the parasite surface; live worms from all intravascular life stages display GAPDH activity. Suppressing GAPDH gene expression using RNA interference significantly lowers this live worm surface activity. Medium in which the worms are cultured overnight displays essentially no activity, showing that the enzyme is not shed or excreted but remains associated with the worm surface. Immunolocalization experiments confirm that the enzyme is highly expressed in the parasite tegument (skin). Surface activity in schistosomula amounts to ∼8% of that displayed by equivalent parasite lysates. To address the functional role of SmGAPDH, we purified the protein following its expression in Escherichia coli strain DS113. The recombinant protein displays optimal enzymatic activity at pH 9.2, shows robust activity at the temperature of the parasite's hosts, and has a Michaelis-Menten constant for glyceraldehyde-3-phosphate (GAP) of 1.4 mM±0.24. We show that recombinant SmGAPDH binds plasminogen (PLMG) and promotes PLMG conversion to its active form (plasmin) in a dose response in the presence of tissue plasminogen activator. Since plasmin is a key mediator of thrombolysis, our results support the hypothesis that SmGAPDH, a host-interactive tegumental protein that can enhance PLMG activation, could help degrade blood clots around the worms in the vascular microenvironment and thus promote parasite survival in vivo. This article has an associated First Person interview with the first author of the paper.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Schistosoma mansoniglyceraldehyde-3-phosphate dehydrogenase enhances formation of the blood-clot lysis protein plasmin

2020

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“…In addition to being widely distributed inside cells, in several instances aldolase has been reported ( Gómez-Arreaza et al, 2014 ; Shams et al, 2014 ; Pirovich et al, 2019 ) to be found on a cell’s exterior membranes, including on the host-exposed surface of many pathogenic organisms (both bacteria and eukaryotic parasites). One of the notable mysteries in the study of moonlighting proteins is that many surface-localized proteins, including aldolase, lack transmembrane domains and signal peptides involved in canonical secretion pathways: bioinformatics analysis of 22 published studies on bacterial surface proteomes revealed that >1,000 of 3,619 proteins found on the cell surface lack such domains ( Wang and Jeffery 2016 ).…”

Section: Evidence For Surface Localization Of Aldolase On Many Pathogensmentioning

confidence: 99%

“…Figure 2 lists the wide variety of organisms that have been demonstrated to possess an extracellular aldolase (left) and instances in which the enzyme has been shown to bind to plasminogen, promoting its activation (right). Pathogens have been reported to use a number of other glycolytic enzymes, including triosephosphate isomerase (TPI), GAPDH, phosphoglycerate mutase (PGM) and enolase, to bind and activate plasminogen ( Pirovich et al, 2019 ; Pirovich et al, 2020 ).…”

Section: Moonlighting Functions Of Aldolase To Aid Pathogen Survivalmentioning

confidence: 99%

Multifunctional Fructose 1,6-Bisphosphate Aldolase as a Therapeutic Target

Pirovich

Da’dara

Skelly

2021

Front. Mol. Biosci.

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Fructose 1,6-bisphosphate aldolase is a ubiquitous cytosolic enzyme that catalyzes the fourth step of glycolysis. Aldolases are classified into three groups: Class-I, Class-IA, and Class-II; all classes share similar structural features but low amino acid identity. Apart from their conserved role in carbohydrate metabolism, aldolases have been reported to perform numerous non-enzymatic functions. Here we review the myriad “moonlighting” functions of this classical enzyme, many of which are centered on its ability to bind to an array of partner proteins that impact cellular scaffolding, signaling, transcription, and motility. In addition to the cytosolic location, aldolase has been found the extracellular surface of several pathogenic bacteria, fungi, protozoans, and metazoans. In the extracellular space, the enzyme has been reported to perform virulence-enhancing moonlighting functions e.g., plasminogen binding, host cell adhesion, and immunomodulation. Aldolase’s importance has made it both a drug target and vaccine candidate. In this review, we note the several inhibitors that have been synthesized with high specificity for the aldolases of pathogens and cancer cells and have been shown to inhibit classical enzyme activity and moonlighting functions. We also review the many trials in which recombinant aldolases have been used as vaccine targets against a wide variety of pathogenic organisms including bacteria, fungi, and metazoan parasites. Most of such trials generated significant protection from challenge infection, correlated with antigen-specific cellular and humoral immune responses. We argue that refinement of aldolase antigen preparations and expansion of immunization trials should be encouraged to promote the advancement of promising, protective aldolase vaccines.

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“…Glyceraldehyde 3-phosphate dehydrogenase (G3PDH) is a cytosolic antigen. Yet, it was readily detected on the surface of S. mansoni 3 h in vitro schistosomula (Goudot-Crozel et al 1989), lung-stage schistosomula (Tallima and El Ridi 2008;Pirovich et al 2019Pirovich et al , 2020, among adult worms surface membrane-associated molecules, and in larval and adult worms excretory-secretory products (ESP) Sotillo et al 2015). Indeed, schistosome G3PDH (SG3PDH) is considered a prominent moonlighting protein.…”

Section: Glyceraldehyde 3-phosphate Dehydrogenasementioning

confidence: 99%