title: A Toxoplasma dense granule protein, GRA24, modulates the early immune response to infection by promoting a direct and sustained host p38 MAPK activation.
abstract: 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 p38α MAP kinase. This noncanonical kinetics of p38α 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-p38α 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.
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), UMR5163, Laboratoire Adaptation et Pathogénie des Microorganismes, F-38041 Grenoble, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Braun
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Brenier-Pinchart
authors.forename: Manickam
authors.initials: M
authors.lastname: Yogavel
authors.forename: Aurélie
authors.initials: A
authors.lastname: Curt-Varesano
authors.forename: Rose-Laurence
authors.initials: RL
authors.lastname: Curt-Bertini
authors.forename: Tahir
authors.initials: T
authors.lastname: Hussain
authors.forename: Sylvie
authors.initials: S
authors.lastname: Kieffer-Jaquinod
authors.forename: Yohann
authors.initials: Y
authors.lastname: Coute
authors.forename: Hervé
authors.initials: H
authors.lastname: Pelloux
authors.forename: Isabelle
authors.initials: I
authors.lastname: Tardieux
authors.forename: Amit
authors.initials: A
authors.lastname: Sharma
authors.forename: Hassan
authors.initials: H
authors.lastname: Belrhali
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bougdour
authors.forename: Mohamed-Ali
authors.initials: MA
authors.lastname: Hakimi
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis; D016000:Cluster Analysis; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D023061:Gene Order; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D021381:Protein Transport; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016415:Sequence Alignment; D014122:Toxoplasma / Q000235:genetics / Q000276:immunology*; D014123:Toxoplasmosis / Q000276:immunology* / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D018925:Chemokines; D051766:Early Growth Response Protein 1; D016760:Proto-Oncogene Proteins c-fos; D015800:Protozoan Proteins; D048051:p38 Mitogen-Activated Protein Kinases
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