A <italic toggle="yes">Toxoplasma</italic> Prolyl Hydroxylase Mediates Oxygen Stress Responses by Regulating Translation Elongation

ABSTRACT As the protozoan parasite Toxoplasma gondii disseminates through its host, it responds to environmental changes by altering its gene expression, metabolism, and other processes. Oxygen is one variable environmental factor, and properly adapting to changes in oxygen levels is critical to pre...

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Autores principales:	Celia Florimond, Charlotte Cordonnier, Rahil Taujale, Hanke van der Wel, Natarajan Kannan, Christopher M. West, Ira J. Blader
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	host-pathogen interactions metabolism oxygen protein translation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/cce39d19a7444b7598a65d908272eb1c
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spelling	oai:doaj.org-article:cce39d19a7444b7598a65d908272eb1c2021-11-15T15:55:24ZA <italic toggle="yes">Toxoplasma</italic> Prolyl Hydroxylase Mediates Oxygen Stress Responses by Regulating Translation Elongation10.1128/mBio.00234-192150-7511https://doaj.org/article/cce39d19a7444b7598a65d908272eb1c2019-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00234-19https://doaj.org/toc/2150-7511ABSTRACT As the protozoan parasite Toxoplasma gondii disseminates through its host, it responds to environmental changes by altering its gene expression, metabolism, and other processes. Oxygen is one variable environmental factor, and properly adapting to changes in oxygen levels is critical to prevent the accumulation of reactive oxygen species and other cytotoxic factors. Thus, oxygen-sensing proteins are important, and among these, 2-oxoglutarate-dependent prolyl hydroxylases are highly conserved throughout evolution. Toxoplasma expresses two such enzymes, TgPHYa, which regulates the SCF-ubiquitin ligase complex, and TgPHYb. To characterize TgPHYb, we created a Toxoplasma strain that conditionally expresses TgPHYb and report that TgPHYb is required for optimal parasite growth under normal growth conditions. However, exposing TgPHYb-depleted parasites to extracellular stress leads to severe decreases in parasite invasion, which is likely due to decreased abundance of parasite adhesins. Adhesin protein abundance is reduced in TgPHYb-depleted parasites as a result of inactivation of the protein synthesis elongation factor eEF2 that is accompanied by decreased rates of translational elongation. In contrast to most other oxygen-sensing proteins that mediate cellular responses to low O2, TgPHYb is specifically required for parasite growth and protein synthesis at high, but not low, O2 tensions as well as resistance to reactive oxygen species. In vivo, reduced TgPHYb expression leads to lower parasite burdens in oxygen-rich tissues. Taken together, these data identify TgPHYb as a sensor of high O2 levels, in contrast to TgPHYa, which supports the parasite at low O2. IMPORTANCE Because oxygen plays a key role in the growth of many organisms, cells must know how much oxygen is available. O2-sensing proteins are therefore critical cellular factors, and prolyl hydroxylases are the best-studied type of O2-sensing proteins. In general, prolyl hydroxylases trigger cellular responses to decreased oxygen availability. But, how does a cell react to high levels of oxygen? Using the protozoan parasite Toxoplasma gondii, we discovered a prolyl hydroxylase that allows the parasite to grow at elevated oxygen levels and does so by regulating protein synthesis. Loss of this enzyme also reduces parasite burden in oxygen-rich tissues, indicating that sensing both high and low levels of oxygen impacts the growth and physiology of Toxoplasma.Celia FlorimondCharlotte CordonnierRahil TaujaleHanke van der WelNatarajan KannanChristopher M. WestIra J. BladerAmerican Society for Microbiologyarticlehost-pathogen interactionsmetabolismoxygenprotein translationMicrobiologyQR1-502ENmBio, Vol 10, Iss 2 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	host-pathogen interactions metabolism oxygen protein translation Microbiology QR1-502
spellingShingle	host-pathogen interactions metabolism oxygen protein translation Microbiology QR1-502 Celia Florimond Charlotte Cordonnier Rahil Taujale Hanke van der Wel Natarajan Kannan Christopher M. West Ira J. Blader A <italic toggle="yes">Toxoplasma</italic> Prolyl Hydroxylase Mediates Oxygen Stress Responses by Regulating Translation Elongation
description	ABSTRACT As the protozoan parasite Toxoplasma gondii disseminates through its host, it responds to environmental changes by altering its gene expression, metabolism, and other processes. Oxygen is one variable environmental factor, and properly adapting to changes in oxygen levels is critical to prevent the accumulation of reactive oxygen species and other cytotoxic factors. Thus, oxygen-sensing proteins are important, and among these, 2-oxoglutarate-dependent prolyl hydroxylases are highly conserved throughout evolution. Toxoplasma expresses two such enzymes, TgPHYa, which regulates the SCF-ubiquitin ligase complex, and TgPHYb. To characterize TgPHYb, we created a Toxoplasma strain that conditionally expresses TgPHYb and report that TgPHYb is required for optimal parasite growth under normal growth conditions. However, exposing TgPHYb-depleted parasites to extracellular stress leads to severe decreases in parasite invasion, which is likely due to decreased abundance of parasite adhesins. Adhesin protein abundance is reduced in TgPHYb-depleted parasites as a result of inactivation of the protein synthesis elongation factor eEF2 that is accompanied by decreased rates of translational elongation. In contrast to most other oxygen-sensing proteins that mediate cellular responses to low O2, TgPHYb is specifically required for parasite growth and protein synthesis at high, but not low, O2 tensions as well as resistance to reactive oxygen species. In vivo, reduced TgPHYb expression leads to lower parasite burdens in oxygen-rich tissues. Taken together, these data identify TgPHYb as a sensor of high O2 levels, in contrast to TgPHYa, which supports the parasite at low O2. IMPORTANCE Because oxygen plays a key role in the growth of many organisms, cells must know how much oxygen is available. O2-sensing proteins are therefore critical cellular factors, and prolyl hydroxylases are the best-studied type of O2-sensing proteins. In general, prolyl hydroxylases trigger cellular responses to decreased oxygen availability. But, how does a cell react to high levels of oxygen? Using the protozoan parasite Toxoplasma gondii, we discovered a prolyl hydroxylase that allows the parasite to grow at elevated oxygen levels and does so by regulating protein synthesis. Loss of this enzyme also reduces parasite burden in oxygen-rich tissues, indicating that sensing both high and low levels of oxygen impacts the growth and physiology of Toxoplasma.
format	article
author	Celia Florimond Charlotte Cordonnier Rahil Taujale Hanke van der Wel Natarajan Kannan Christopher M. West Ira J. Blader
author_facet	Celia Florimond Charlotte Cordonnier Rahil Taujale Hanke van der Wel Natarajan Kannan Christopher M. West Ira J. Blader
author_sort	Celia Florimond
title	A <italic toggle="yes">Toxoplasma</italic> Prolyl Hydroxylase Mediates Oxygen Stress Responses by Regulating Translation Elongation
title_short	A <italic toggle="yes">Toxoplasma</italic> Prolyl Hydroxylase Mediates Oxygen Stress Responses by Regulating Translation Elongation
title_full	A <italic toggle="yes">Toxoplasma</italic> Prolyl Hydroxylase Mediates Oxygen Stress Responses by Regulating Translation Elongation
title_fullStr	A <italic toggle="yes">Toxoplasma</italic> Prolyl Hydroxylase Mediates Oxygen Stress Responses by Regulating Translation Elongation
title_full_unstemmed	A <italic toggle="yes">Toxoplasma</italic> Prolyl Hydroxylase Mediates Oxygen Stress Responses by Regulating Translation Elongation
title_sort	<italic toggle="yes">toxoplasma</italic> prolyl hydroxylase mediates oxygen stress responses by regulating translation elongation
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/cce39d19a7444b7598a65d908272eb1c
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A <italic toggle="yes">Toxoplasma</italic> Prolyl Hydroxylase Mediates Oxygen Stress Responses by Regulating Translation Elongation

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