Exported Epoxide Hydrolases Modulate Erythrocyte Vasoactive Lipids during <named-content content-type="genus-species">Plasmodium falciparum</named-content> Infection

ABSTRACT Erythrocytes are reservoirs of important epoxide-containing lipid signaling molecules, including epoxyeicosatrienoic acids (EETs). EETs function as vasodilators and anti-inflammatory modulators in the bloodstream. Bioactive EETs are hydrolyzed to less active diols (dihydroxyeicosatrienoic a...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Natalie J. Spillman, Varun K. Dalmia, Daniel E. Goldberg
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/3e606cfd06664d5bacbd165b2cacc9b5
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:3e606cfd06664d5bacbd165b2cacc9b5
record_format	dspace
spelling	oai:doaj.org-article:3e606cfd06664d5bacbd165b2cacc9b52021-11-15T15:50:15ZExported Epoxide Hydrolases Modulate Erythrocyte Vasoactive Lipids during <named-content content-type="genus-species">Plasmodium falciparum</named-content> Infection10.1128/mBio.01538-162150-7511https://doaj.org/article/3e606cfd06664d5bacbd165b2cacc9b52016-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01538-16https://doaj.org/toc/2150-7511ABSTRACT Erythrocytes are reservoirs of important epoxide-containing lipid signaling molecules, including epoxyeicosatrienoic acids (EETs). EETs function as vasodilators and anti-inflammatory modulators in the bloodstream. Bioactive EETs are hydrolyzed to less active diols (dihydroxyeicosatrienoic acids) by epoxide hydrolases (EHs). The malaria parasite Plasmodium falciparum infects host red blood cells (RBCs) and exports hundreds of proteins into the RBC compartment. In this study, we show that two parasite epoxide hydrolases, P. falciparum epoxide hydrolases 1 (PfEH1) and 2 (PfEH2), both with noncanonical serine nucleophiles, are exported to the periphery of infected RBCs. PfEH1 and PfEH2 were successfully expressed in Escherichia coli, and they hydrolyzed physiologically relevant erythrocyte EETs. Mutations in active site residues of PfEH1 ablated the ability of the enzyme to hydrolyze an epoxide substrate. Overexpression of PfEH1 or PfEH2 in parasite-infected RBCs resulted in a significant alteration in the epoxide fatty acids stored in RBC phospholipids. We hypothesize that the parasite disruption of epoxide-containing signaling lipids leads to perturbed vascular function, creating favorable conditions for binding and sequestration of infected RBCs to the microvascular endothelium. IMPORTANCE The malaria parasite exports hundreds of proteins into the erythrocyte compartment. However, for most of these proteins, their physiological function is unknown. In this study, we investigate two “hypothetical” proteins of the α/β-hydrolase fold family that share sequence similarity with epoxide hydrolases (EHs)—enzymes that destroy bioactive epoxides. Altering EH expression in parasite-infected erythrocytes resulted in a significant change in the epoxide fatty acids stored in the host cell. We propose that these EH enzymes may help the parasite to manipulate host blood vessel opening and inflame the vessel walls as they pass through the circulation system. Understanding how the malaria parasite interacts with its host RBCs will aid in our ability to combat this deadly disease.Natalie J. SpillmanVarun K. DalmiaDaniel E. GoldbergAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 5 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Natalie J. Spillman Varun K. Dalmia Daniel E. Goldberg Exported Epoxide Hydrolases Modulate Erythrocyte Vasoactive Lipids during <named-content content-type="genus-species">Plasmodium falciparum</named-content> Infection
description	ABSTRACT Erythrocytes are reservoirs of important epoxide-containing lipid signaling molecules, including epoxyeicosatrienoic acids (EETs). EETs function as vasodilators and anti-inflammatory modulators in the bloodstream. Bioactive EETs are hydrolyzed to less active diols (dihydroxyeicosatrienoic acids) by epoxide hydrolases (EHs). The malaria parasite Plasmodium falciparum infects host red blood cells (RBCs) and exports hundreds of proteins into the RBC compartment. In this study, we show that two parasite epoxide hydrolases, P. falciparum epoxide hydrolases 1 (PfEH1) and 2 (PfEH2), both with noncanonical serine nucleophiles, are exported to the periphery of infected RBCs. PfEH1 and PfEH2 were successfully expressed in Escherichia coli, and they hydrolyzed physiologically relevant erythrocyte EETs. Mutations in active site residues of PfEH1 ablated the ability of the enzyme to hydrolyze an epoxide substrate. Overexpression of PfEH1 or PfEH2 in parasite-infected RBCs resulted in a significant alteration in the epoxide fatty acids stored in RBC phospholipids. We hypothesize that the parasite disruption of epoxide-containing signaling lipids leads to perturbed vascular function, creating favorable conditions for binding and sequestration of infected RBCs to the microvascular endothelium. IMPORTANCE The malaria parasite exports hundreds of proteins into the erythrocyte compartment. However, for most of these proteins, their physiological function is unknown. In this study, we investigate two “hypothetical” proteins of the α/β-hydrolase fold family that share sequence similarity with epoxide hydrolases (EHs)—enzymes that destroy bioactive epoxides. Altering EH expression in parasite-infected erythrocytes resulted in a significant change in the epoxide fatty acids stored in the host cell. We propose that these EH enzymes may help the parasite to manipulate host blood vessel opening and inflame the vessel walls as they pass through the circulation system. Understanding how the malaria parasite interacts with its host RBCs will aid in our ability to combat this deadly disease.
format	article
author	Natalie J. Spillman Varun K. Dalmia Daniel E. Goldberg
author_facet	Natalie J. Spillman Varun K. Dalmia Daniel E. Goldberg
author_sort	Natalie J. Spillman
title	Exported Epoxide Hydrolases Modulate Erythrocyte Vasoactive Lipids during <named-content content-type="genus-species">Plasmodium falciparum</named-content> Infection
title_short	Exported Epoxide Hydrolases Modulate Erythrocyte Vasoactive Lipids during <named-content content-type="genus-species">Plasmodium falciparum</named-content> Infection
title_full	Exported Epoxide Hydrolases Modulate Erythrocyte Vasoactive Lipids during <named-content content-type="genus-species">Plasmodium falciparum</named-content> Infection
title_fullStr	Exported Epoxide Hydrolases Modulate Erythrocyte Vasoactive Lipids during <named-content content-type="genus-species">Plasmodium falciparum</named-content> Infection
title_full_unstemmed	Exported Epoxide Hydrolases Modulate Erythrocyte Vasoactive Lipids during <named-content content-type="genus-species">Plasmodium falciparum</named-content> Infection
title_sort	exported epoxide hydrolases modulate erythrocyte vasoactive lipids during <named-content content-type="genus-species">plasmodium falciparum</named-content> infection
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/3e606cfd06664d5bacbd165b2cacc9b5
work_keys_str_mv	AT nataliejspillman exportedepoxidehydrolasesmodulateerythrocytevasoactivelipidsduringnamedcontentcontenttypegenusspeciesplasmodiumfalciparumnamedcontentinfection AT varunkdalmia exportedepoxidehydrolasesmodulateerythrocytevasoactivelipidsduringnamedcontentcontenttypegenusspeciesplasmodiumfalciparumnamedcontentinfection AT danielegoldberg exportedepoxidehydrolasesmodulateerythrocytevasoactivelipidsduringnamedcontentcontenttypegenusspeciesplasmodiumfalciparumnamedcontentinfection
_version_	1718427453789044736

Exported Epoxide Hydrolases Modulate Erythrocyte Vasoactive Lipids during <named-content content-type="genus-species">Plasmodium falciparum</named-content> Infection

Ejemplares similares