<italic toggle="yes">Toxoplasma</italic> Controls Host Cyclin E Expression through the Use of a Novel MYR1-Dependent Effector Protein, HCE1

ABSTRACT Toxoplasma gondii is an obligate intracellular parasite that establishes a favorable environment in the host cells in which it replicates. We have previously reported that it uses MYR-dependent translocation of dense granule proteins to elicit a key set of host responses related to the cell...

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Autores principales:	Michael W. Panas, Adit Naor, Alicja M. Cygan, John C. Boothroyd
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	effector proteins Toxoplasma host-pathogen interactions microbiology Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0543cb72aca946c39f860e0ac282d6b4
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spelling	oai:doaj.org-article:0543cb72aca946c39f860e0ac282d6b42021-11-15T15:55:25Z<italic toggle="yes">Toxoplasma</italic> Controls Host Cyclin E Expression through the Use of a Novel MYR1-Dependent Effector Protein, HCE110.1128/mBio.00674-192150-7511https://doaj.org/article/0543cb72aca946c39f860e0ac282d6b42019-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00674-19https://doaj.org/toc/2150-7511ABSTRACT Toxoplasma gondii is an obligate intracellular parasite that establishes a favorable environment in the host cells in which it replicates. We have previously reported that it uses MYR-dependent translocation of dense granule proteins to elicit a key set of host responses related to the cell cycle, specifically, E2F transcription factor targets, including cyclin E. We report here the identification of a novel Toxoplasma effector protein that is exported from the parasitophorous vacuole in a MYR1-dependent manner and localizes to the host’s nucleus. Parasites lacking this inducer of host cyclin E (HCE1) are unable to modulate E2F transcription factor target genes and exhibit a substantial growth defect. Immunoprecipitation of HCE1 from infected host cells showed that HCE1 efficiently binds elements of the cyclin E regulatory complex, namely, DP1 and its partners E2F3 and E2F4. Expression of HCE1 in Neospora caninum, or in uninfected human foreskin fibroblasts (HFFs), showed localization of the expressed protein to the host nuclei and strong cyclin E upregulation. Thus, HCE1 is a novel effector protein that is necessary and sufficient to impact the E2F axis of transcription, resulting in co-opting of host functions to the advantage of Toxoplasma. IMPORTANCE Like most Apicomplexan parasites, Toxoplasma gondii has the remarkable ability to invade and establish a replicative niche within another eukaryotic cell, in this case, any of a large number of cell types in almost any warm-blooded animals. Part of the process of establishing this niche is the export of effector proteins to co-opt host cell functions in favor of the parasite. Here we identify a novel effector protein, HCE1, that the parasites export into the nucleus of human cells, where it modulates the expression of multiple genes, including the gene encoding cyclin E, one of the most crucial proteins involved in controlling when and whether a human cell divides. We show that HCE1 works through binding to specific transcription factors, namely, E2F3, E2F4, and DP1, that normally carefully regulate these all-important pathways. This represents a new way in which these consummately efficient infectious agents co-opt the human cells that they so efficiently grow within.Michael W. PanasAdit NaorAlicja M. CyganJohn C. BoothroydAmerican Society for Microbiologyarticleeffector proteinsToxoplasmahost-pathogen interactionsmicrobiologyMicrobiologyQR1-502ENmBio, Vol 10, Iss 2 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	effector proteins Toxoplasma host-pathogen interactions microbiology Microbiology QR1-502
spellingShingle	effector proteins Toxoplasma host-pathogen interactions microbiology Microbiology QR1-502 Michael W. Panas Adit Naor Alicja M. Cygan John C. Boothroyd <italic toggle="yes">Toxoplasma</italic> Controls Host Cyclin E Expression through the Use of a Novel MYR1-Dependent Effector Protein, HCE1
description	ABSTRACT Toxoplasma gondii is an obligate intracellular parasite that establishes a favorable environment in the host cells in which it replicates. We have previously reported that it uses MYR-dependent translocation of dense granule proteins to elicit a key set of host responses related to the cell cycle, specifically, E2F transcription factor targets, including cyclin E. We report here the identification of a novel Toxoplasma effector protein that is exported from the parasitophorous vacuole in a MYR1-dependent manner and localizes to the host’s nucleus. Parasites lacking this inducer of host cyclin E (HCE1) are unable to modulate E2F transcription factor target genes and exhibit a substantial growth defect. Immunoprecipitation of HCE1 from infected host cells showed that HCE1 efficiently binds elements of the cyclin E regulatory complex, namely, DP1 and its partners E2F3 and E2F4. Expression of HCE1 in Neospora caninum, or in uninfected human foreskin fibroblasts (HFFs), showed localization of the expressed protein to the host nuclei and strong cyclin E upregulation. Thus, HCE1 is a novel effector protein that is necessary and sufficient to impact the E2F axis of transcription, resulting in co-opting of host functions to the advantage of Toxoplasma. IMPORTANCE Like most Apicomplexan parasites, Toxoplasma gondii has the remarkable ability to invade and establish a replicative niche within another eukaryotic cell, in this case, any of a large number of cell types in almost any warm-blooded animals. Part of the process of establishing this niche is the export of effector proteins to co-opt host cell functions in favor of the parasite. Here we identify a novel effector protein, HCE1, that the parasites export into the nucleus of human cells, where it modulates the expression of multiple genes, including the gene encoding cyclin E, one of the most crucial proteins involved in controlling when and whether a human cell divides. We show that HCE1 works through binding to specific transcription factors, namely, E2F3, E2F4, and DP1, that normally carefully regulate these all-important pathways. This represents a new way in which these consummately efficient infectious agents co-opt the human cells that they so efficiently grow within.
format	article
author	Michael W. Panas Adit Naor Alicja M. Cygan John C. Boothroyd
author_facet	Michael W. Panas Adit Naor Alicja M. Cygan John C. Boothroyd
author_sort	Michael W. Panas
title	<italic toggle="yes">Toxoplasma</italic> Controls Host Cyclin E Expression through the Use of a Novel MYR1-Dependent Effector Protein, HCE1
title_short	<italic toggle="yes">Toxoplasma</italic> Controls Host Cyclin E Expression through the Use of a Novel MYR1-Dependent Effector Protein, HCE1
title_full	<italic toggle="yes">Toxoplasma</italic> Controls Host Cyclin E Expression through the Use of a Novel MYR1-Dependent Effector Protein, HCE1
title_fullStr	<italic toggle="yes">Toxoplasma</italic> Controls Host Cyclin E Expression through the Use of a Novel MYR1-Dependent Effector Protein, HCE1
title_full_unstemmed	<italic toggle="yes">Toxoplasma</italic> Controls Host Cyclin E Expression through the Use of a Novel MYR1-Dependent Effector Protein, HCE1
title_sort	<italic toggle="yes">toxoplasma</italic> controls host cyclin e expression through the use of a novel myr1-dependent effector protein, hce1
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/0543cb72aca946c39f860e0ac282d6b4
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<italic toggle="yes">Toxoplasma</italic> Controls Host Cyclin E Expression through the Use of a Novel MYR1-Dependent Effector Protein, HCE1

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