Title: Toxoplasma gondii – a master manipulator: From effectordiscovery to novel concepts in cell death.
Abstract: Toxoplasma gondii translocates effector proteins into its host cell tosubvert various host pathways. T. gondii effector TgIST blocks thetranscription of interferon-stimulated genes to reduce immune defense.Interferons upregulate numerous genes, including protein kinase R (PKR), whichinduce necrosome formation to activate mixed-lineage-kinase-domain-like (MLKL)pseudokinase and induce necroptosis. Whether these interferon functions aretargeted by Toxoplasma is unknown. Here, we examine secreted effectors thatlocalize to the host cell nucleus and find that the chronic bradyzoite stagesecretes effector TgNSM that targets the NCoR/SMRT complex, a repressor forvarious transcription factors, to inhibit interferon-regulated genes involvedin cell death. TgNSM acts with TgIST to block IFN-driven expression of PKR andMLKL, thus preventing host cell necroptotic death and protecting the parasite’sintracellular niche. The mechanism of action of TgNSM uncovers a role ofNCoR/SMRT in necroptosis, assuring survival of intracellular cysts and chronicinfection.
Host: Beni Podbilewicz
