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bioRxiv · 10.1101/2020.08.31.275339

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

Rosenburg, A.·Sibley, L. D.
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Abstract

During infection, Toxoplasma gondii translocates effector proteins directly into its host cell to subvert various signaling pathways. Here we characterize a novel secreted effector that localizes to the host cell nucleus where it modulates NCoR/SMRT repressor complex levels to repress interferon regulated genes involved in cell death. Type I and type II interferons upregulate many genes including protein kinase R (PKR), inducing formation of the necrosome complex that activates Mixed Lineage Kinase Domain Like Pseudokinase (MLKL) to execute necrotic cell death. Toxoplasma NCoR/SMRT modulator (TgNSM) acts together with another secreted effector TgIST, previously shown to down-modulate IFN-{gamma} signaling to block immune functions. Together TgNSM and TgIST block IFN driven expression of PKR and MLKL, thus preventing host cell necroptotic death. The mechanism of action of TgNSM highlights a previously unappreciated role of NCoR/SMRT in regulation of necroptosis, assuring survival of intracellular cysts, and maintenance of chronic infection.

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Rosenburg, A., Sibley, L. D.. 2020-08-31. Toxoplasma gondii secreted effectors co-opt host repressor complexes to inhibit necroptosis. https://doi.org/10.1101/2020.08.31.275339

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