title: Host and parasite-derived IKK activities direct distinct temporal phases of NF-kappaB activation and target gene expression following Toxoplasma gondii infection.
abstract: Activation of NF-kappaB by the intracellular pathogen Toxoplasma gondii is associated with the localization of phosphorylated IkappaB alpha to the parasitophorous vacuole membrane (PVM). This is mediated by a parasite-derived IkappaB kinase (TgIKK) activity and is independent of host IKK function. In the present study, we examined the roles of host IKK and parasite-derived TgIKK on the temporal modulation of NF-kappaB activation. Despite the presence of TgIKK activity at the PVM, nuclear translocation of NF-kappaB and subsequent gene expression exhibited a requirement for the host IKK complex. A detailed kinetic analysis of NF-kappaB activation revealed a biphasic, hierarchical and temporally regulated response. We propose a novel paradigm for the modulation of NF-kappaB-dependent gene expression by T. gondii that involves both the host IKK complex and TgIKK activity at different phases of infection. Thus, T. gondii effectively alters gene expression in a temporal dimension by exploiting the NF-kappaB signaling machinery and subsequently rewiring the activation circuits of the infected host cell.
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Molestina
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Sinai
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation; D006790:Host-Parasite Interactions; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D015800:Protozoan Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014122:Toxoplasma / Q000166:cytology / Q000201:enzymology*; D014123:Toxoplasmosis / Q000201:enzymology* / Q000473:pathology; D014617:Vacuoles / Q000201:enzymology / Q000469:parasitology; D014709:Vero Cells
chemical_list: D016328:NF-kappa B; D015800:Protozoan Proteins; D051550:I-kappa B Kinase