Toxoplasma gondii secreted effectors co-opt host repressor complexes to inhibit necroptosis
Alex Rosenberg1, L David Sibley1
1Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63130, USA.
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.
Insights
Toxoplasma gondii uses effector TgNSM to block host cell death pathways, preventing immune responses. This mechanism, involving the NCoR/SMRT complex, ensures parasite survival during chronic infections.
Area of Science:
- Parasitology
- Immunology
- Cell Biology
Background:
- Toxoplasma gondii manipulates host cells using effector proteins.
- Interferons activate host defenses, including necroptosis, a form of programmed cell death.
- The role of T. gondii effectors in targeting interferon-induced cell death pathways was unclear.
Purpose of the Study:
- To investigate secreted T. gondii effectors that target host cell nucleus.
- To determine if T. gondii inhibits interferon-driven necroptosis.
- To elucidate the mechanism by which T. gondii ensures survival in host cells.
Main Methods:
- Analysis of secreted effector proteins localizing to the host cell nucleus.
- Investigating the interaction of T. gondii effectors with host transcription factors and complexes.
- Assessing the impact of effectors on interferon-stimulated gene expression and host cell death.
Main Results:
- The bradyzoite effector TgNSM targets the NCoR/SMRT complex, inhibiting interferon-regulated genes.
- TgNSM collaborates with TgIST to suppress the expression of protein kinase R (PKR) and MLKL.
- This inhibition prevents host cell necroptosis, protecting the parasite's niche.
Conclusions:
- T. gondii effector TgNSM inhibits host necroptosis by targeting the NCoR/SMRT complex.
- TgNSM and TgIST cooperate to block interferon-mediated cell death, ensuring parasite survival.
- This study reveals a novel role for NCoR/SMRT in necroptosis and T. gondii chronic infection.
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