Toxoplasma gondii secreted effectors co-opt host repressor complexes to inhibit necroptosis

Abstract

Toxoplasma gondii translocates effector proteins into its host cell to subvert various host pathways. T.gondii effector TgIST blocks the transcription of interferon-stimulated genes to reduce immune defense. Interferons upregulate numerous genes, including protein kinase R (PKR), which induce necrosome formation to activate mixed-lineage-kinase-domain-like (MLKL) pseudokinase and induce necroptosis. Whether these interferon functions are targeted by Toxoplasma is unknown. Here, we examine secreted effectors that localize to the host cell nucleus and find that the chronic bradyzoite stage secretes effector TgNSM that targets the NCoR/SMRT complex, a repressor for various transcription factors, to inhibit interferon-regulated genes involved in cell death. TgNSM acts with TgIST to block IFN-driven expression of PKR and MLKL, thus preventing host cell necroptotic death and protecting the parasite's intracellular niche. The mechanism of action of TgNSM uncovers a role of NCoR/SMRT in necroptosis, assuring survival of intracellular cysts and chronic infection.