Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 210, Issue 10, Pages 2071-2086Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20130103
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Funding
- ANR grant ANR Blanc APImiR [ANR 2010 BLAN 1315 01]
- ANR grant ANR Jeune Chercheur ToxoEffect [ANR-12-JSV3-0004-01]
- Laboratoire d'Excellence (LabEx) ParaFrap [ANR-11-LABX-0024]
- FINOVI foundation
- Agence Nationale de la Recherche (ANR) [ANR-12-JSV3-0004] Funding Source: Agence Nationale de la Recherche (ANR)
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Toxoplasma gondii, the causative agent of toxoplasmosis, is an obligate intracellular protozoan parasite that resides inside a parasitophorous vacuole. During infection, Toxoplasma actively remodels the transcriptome of its hosting cells with profound and coupled impact on the host immune response. We report that Toxoplasma secretes GRA24, a novel dense granule protein which traffics from the vacuole to the host cell nucleus. Once released into the host cell, GRA24 has the unique ability to trigger prolonged autophosphorylation and nuclear translocation of the host cell p38 alpha MAP kinase. This noncanonical kinetics of p38 alpha activation correlates with the up-regulation of the transcription factors Egr-1 and c-Fos and the correlated synthesis of key proinflammatory cytokines, including interleukin-12 and the chemokine MCP-1, both known to control early parasite replication in vivo. Remarkably, the GRA24-p38 alpha complex is defined by peculiar structural features and uncovers a new regulatory signaling path distinct from the MAPK signaling cascade and otherwise commonly activated by stress-related stimuli or various intracellular microbes.
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