Characterization of a Toxoplasma effector uncovers an alternative GSK3/β-catenin-regulatory pathway of inflammation
- Université Grenoble Alpes, France
Abstract
The intracellular parasite Toxoplasma gondii, hijacks evolutionarily conserved host processes by delivering effector proteins into the host cell that shift gene expression in a timely fashion. We identified a parasite dense granule protein as GRA18 that once released in the host cell cytoplasm forms versatile complexes with regulatory elements of the β-catenin destruction complex. By interacting with GSK3/PP2A-B56, GRA18 drives β-catenin up-regulation and the downstream effects on host cell gene expression. In the context of macrophages infection, GRA18 induces the expression of a specific set of genes commonly associated with an anti-inflammatory response that includes those encoding chemokines CCL17 and CCL22. Overall, this study adds another original strategy by which T. gondii tachyzoites reshuffle the host cell interactome through a GSK3/β-catenin axis to selectively reprogram immune gene expression.
Data availability
Datasets Generated: Transcriptomic analysis by Next Generation Sequencing (RNA-seq) have been deposited in GEO under accession code GSE103113.
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Transcriptomic analysis by Next Generation Sequencing of mouse bone marrow derived macrophages (BMDMs) infected by Wild-Type and gra18 mutant strains of T. gondii.Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE103113).
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Toxoplasma gondii Transcriptome or Gene expressionSRP008923 and SRP011061.
Article and author information
Author details
Mohamed-ali Hakimi
Alexandre Bougdour
Funding
Agence Nationale de la Recherche (ANR-12-JSV3-0004-01)
- Alexandre Bougdour
European Commission (ERC Consolidator Grant No. 614880)
- Laurence Braun
- Mohamed-ali Hakimi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed under pathogen-free conditions in accordance with established institutional guidance and approved protocols from the institutional animal care and use committee protocol (#175_UHTA-UMR5163-AB-01) of the University Grenoble Alpes. For all the experiments performed, every effort was made to minimize suffering.
Reviewing Editor
- Dominique Soldati-Favre, University of Geneva, Switzerland
Version history
- Received: July 6, 2018
- Accepted: October 14, 2018
- Accepted Manuscript published: October 15, 2018 (version 1)
- Version of Record published: November 2, 2018 (version 2)
Copyright
© 2018, He et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Characterization of a Toxoplasma effector uncovers an alternative GSK3/β-catenin-regulatory pathway of inflammation
eLife 7:e39887.
https://doi.org/10.7554/eLife.39887
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