A Toxoplasma dense granule protein, GRA24, modulates the early immune response to infection by promoting a direct and sustained host p38 MAPK activation

• DOI: 10.1084/jem.20130103
• Publication Date: 2013-09-17T03:04:30Z
• Authors: Laurence Braun; Marie-Pierre Bren...; Manickam Yogavel; Aurélie Curt-Vare...; Rose-Laurence Cur...; Tahir Hussain; Sylvie Kieffer-Ja...; Yohann Coute; Hervé Pelloux; Isabelle Tardieux; Amit Sharma; Hassan Belrhali; Alexandre Bougdour; Mohamed-Ali Hakimi
• Keywords: Intracellular parasite; Proinflammatory cytokine; Stress granule; Dense granule

Toxoplasma gondii, the causative agent of toxoplasmosis, is an obligate intracellular protozoan parasite that resides inside a parasitophorous vacuole. During infection, actively remodels transcriptome its hosting cells with profound and coupled impact on host immune response. We report secretes GRA24, novel dense granule protein which traffics from vacuole to cell nucleus. Once released into cell, GRA24 has unique ability trigger prolonged autophosphorylation nuclear translocation p38α MAP kinase. This noncanonical kinetics activation correlates up-regulation transcription factors Egr-1 c-Fos correlated synthesis key proinflammatory cytokines, including interleukin-12 chemokine MCP-1, both known control early replication in vivo. Remarkably, GRA24–p38α complex defined by peculiar structural features uncovers new regulatory signaling path distinct MAPK cascade otherwise commonly activated stress-related stimuli or various microbes.