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Toxoplasma gondii ROP16 kinase silences the cyclin B1 gene promoter by hijacking host cell UHRF1-dependent epigenetic pathways

Toxoplasmosis, caused by the apicomplexan parasite Toxoplasma gondii, is one of the most common infections in the world due to the lifelong persistence of this parasite in a latent stage. This parasite hijacks host signaling pathways through epigenetic mechanisms which converge on key nuclear protei...

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Autores principales: Sabou, Marcela, Doderer-Lang, Cécile, Leyer, Caroline, Konjic, Ana, Kubina, Sophie, Lennon, Sarah, Rohr, Olivier, Viville, Stéphane, Cianférani, Sarah, Candolfi, Ermanno, Pfaff, Alexander W., Brunet, Julie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256068/
https://www.ncbi.nlm.nih.gov/pubmed/31492965
http://dx.doi.org/10.1007/s00018-019-03267-2
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author Sabou, Marcela
Doderer-Lang, Cécile
Leyer, Caroline
Konjic, Ana
Kubina, Sophie
Lennon, Sarah
Rohr, Olivier
Viville, Stéphane
Cianférani, Sarah
Candolfi, Ermanno
Pfaff, Alexander W.
Brunet, Julie
author_facet Sabou, Marcela
Doderer-Lang, Cécile
Leyer, Caroline
Konjic, Ana
Kubina, Sophie
Lennon, Sarah
Rohr, Olivier
Viville, Stéphane
Cianférani, Sarah
Candolfi, Ermanno
Pfaff, Alexander W.
Brunet, Julie
author_sort Sabou, Marcela
collection PubMed
description Toxoplasmosis, caused by the apicomplexan parasite Toxoplasma gondii, is one of the most common infections in the world due to the lifelong persistence of this parasite in a latent stage. This parasite hijacks host signaling pathways through epigenetic mechanisms which converge on key nuclear proteins. Here, we report a new parasite persistence strategy involving T. gondii rhoptry protein ROP16 secreted early during invasion, which targets the transcription factor UHRF1 (ubiquitin-like containing PHD and RING fingers domain 1), and leads to host cell cycle arrest. This is mediated by DNMT activity and chromatin remodeling at the cyclin B1 gene promoter through recruitment of phosphorylated UHRF1 associated with a repressive multienzymatic protein complex. This leads to deacetylation and methylation of histone H3 surrounding the cyclin B1 promoter to epigenetically silence its transcriptional activity. Moreover, T. gondii infection causes DNA hypermethylation in its host cell, by upregulation of DNMTs. ROP16 is already known to activate and phosphorylate protective immunity transcription factors such as STAT 3/6/5 and modulate host signaling pathways in a strain-dependent manner. Like in the case of STAT6, the strain-dependent effects of ROP16 on UHRF1 are dependent on a single amino-acid polymorphism in ROP16. This study demonstrates that Toxoplasma hijacks a new epigenetic initiator, UHRF1, through an early event initiated by the ROP16 parasite kinase. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00018-019-03267-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-72560682020-06-08 Toxoplasma gondii ROP16 kinase silences the cyclin B1 gene promoter by hijacking host cell UHRF1-dependent epigenetic pathways Sabou, Marcela Doderer-Lang, Cécile Leyer, Caroline Konjic, Ana Kubina, Sophie Lennon, Sarah Rohr, Olivier Viville, Stéphane Cianférani, Sarah Candolfi, Ermanno Pfaff, Alexander W. Brunet, Julie Cell Mol Life Sci Original Article Toxoplasmosis, caused by the apicomplexan parasite Toxoplasma gondii, is one of the most common infections in the world due to the lifelong persistence of this parasite in a latent stage. This parasite hijacks host signaling pathways through epigenetic mechanisms which converge on key nuclear proteins. Here, we report a new parasite persistence strategy involving T. gondii rhoptry protein ROP16 secreted early during invasion, which targets the transcription factor UHRF1 (ubiquitin-like containing PHD and RING fingers domain 1), and leads to host cell cycle arrest. This is mediated by DNMT activity and chromatin remodeling at the cyclin B1 gene promoter through recruitment of phosphorylated UHRF1 associated with a repressive multienzymatic protein complex. This leads to deacetylation and methylation of histone H3 surrounding the cyclin B1 promoter to epigenetically silence its transcriptional activity. Moreover, T. gondii infection causes DNA hypermethylation in its host cell, by upregulation of DNMTs. ROP16 is already known to activate and phosphorylate protective immunity transcription factors such as STAT 3/6/5 and modulate host signaling pathways in a strain-dependent manner. Like in the case of STAT6, the strain-dependent effects of ROP16 on UHRF1 are dependent on a single amino-acid polymorphism in ROP16. This study demonstrates that Toxoplasma hijacks a new epigenetic initiator, UHRF1, through an early event initiated by the ROP16 parasite kinase. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00018-019-03267-2) contains supplementary material, which is available to authorized users. Springer International Publishing 2019-09-06 2020 /pmc/articles/PMC7256068/ /pubmed/31492965 http://dx.doi.org/10.1007/s00018-019-03267-2 Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Article
Sabou, Marcela
Doderer-Lang, Cécile
Leyer, Caroline
Konjic, Ana
Kubina, Sophie
Lennon, Sarah
Rohr, Olivier
Viville, Stéphane
Cianférani, Sarah
Candolfi, Ermanno
Pfaff, Alexander W.
Brunet, Julie
Toxoplasma gondii ROP16 kinase silences the cyclin B1 gene promoter by hijacking host cell UHRF1-dependent epigenetic pathways
title Toxoplasma gondii ROP16 kinase silences the cyclin B1 gene promoter by hijacking host cell UHRF1-dependent epigenetic pathways
title_full Toxoplasma gondii ROP16 kinase silences the cyclin B1 gene promoter by hijacking host cell UHRF1-dependent epigenetic pathways
title_fullStr Toxoplasma gondii ROP16 kinase silences the cyclin B1 gene promoter by hijacking host cell UHRF1-dependent epigenetic pathways
title_full_unstemmed Toxoplasma gondii ROP16 kinase silences the cyclin B1 gene promoter by hijacking host cell UHRF1-dependent epigenetic pathways
title_short Toxoplasma gondii ROP16 kinase silences the cyclin B1 gene promoter by hijacking host cell UHRF1-dependent epigenetic pathways
title_sort toxoplasma gondii rop16 kinase silences the cyclin b1 gene promoter by hijacking host cell uhrf1-dependent epigenetic pathways
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256068/
https://www.ncbi.nlm.nih.gov/pubmed/31492965
http://dx.doi.org/10.1007/s00018-019-03267-2
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