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The antiviral nuclear body protein SP140 represses Ifnb1 transcript stabilization by the novel regulator RESIST [RNA-seq]

ABSTRACT: Negative regulation of the antiviral cytokine IFN-I is critical to prevent host pathology, but is not fully understood. The highly conserved but understudied epigenetic reader and nuclear body protein SP140 represses IFN-I by an unknown mechanism. We describe the mechanism by which SP140 negatively regulates IFN-I, and include RNA-seq of IFNAR KO and SP140 KO IFNAR KO BMMs untreated or treated with 10 ug/mL DMXAA for 4 hours in this dataset. We found that SP140 represses the expression of a novel positive regulator of IFN-I previously annotated as an annexin II receptor, which we rename RESIST (REgulated Stimulator of IFN-I via Stabilization of Transcript). RESIST promotes IFN-I mRNA stability by binding the CCR4-NOT mRNA deadenylase complex and blocking recruitment of the TTP family of RNA-binding proteins, which negatively regulate IFN-I mRNA stability, to CCR4-NOT. Mechanistically, RESIST uses N and C-terminal alpha-helices respectively to either dock to the CCR4-NOT complex or block TTP family binding. Our work reveals a new regulator of IFN-I and a new mechanism regulating IFN-I mRNA stability.

ORGANISM(S): Mus musculus

PROVIDER: GSE269761 | GEO | 2024/08/28

REPOSITORIES: GEO

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Project description:To investigate the early host response triggered by three different strains of Trypanosoma cruzi at a local infection site, changes in host gene expression were monitored in a murine intradermal infection model using Affymetrix oligonucleotide arrays. Robust induction of IFN-stimulated genes (ISGs) was observed in excised skin 24 hours post-infection where the level of ISG induction was parasite strain-dependent with the least virulent strain triggering a muted IFN response. Infection of mice immunodepleted of IFNÎ³-producing cells or infection of IFNÎ³-deficient mice had minimal impact on the IFN response generated in T. cruzi infected mice. In contrast, infection of mice lacking the type I IFN receptor demonstrated that type I IFNs are largely responsible for the IFN response generated at the site of infection. These data highlight type I IFNs as important components of the innate immune response to T. cruzi the site of inoculation and their role in shaping the early transcriptional response to this pathogen. We used microarrays to detail the local host transcriptional response to intradermal T. cruzi infection in WT mice and mice depleted of NK cells, or deficient in IFN-gamma or type I IFN responses. Additionally we compared the local host-transcriptional response generated to infection with 3 different strains of Trypanosoma cruzi (Y, Brazil, and G). Experiment Overall Design: Mice were infected by intradermal injection of 10^6 T. cruzi trypomastigotes in 100uL of saline split between 2 adjacent sites on the shaved side flank. Control mice were injected with an equal volume of saline. 24 hours post-injection approximately 75mm^2 of skin immediately surrounding the injection site was excised and RNA was isolated from the tissue. Balb/c mice were used for most experiments and IFN-gamma KO mice were on the Balb/c background. WT 129 mice were also used as IFNAR-/- mice were on the 129 background. In total 33 arrays were performed. 7 WT (Balb/c) control, 3 Y strain infected, 3 Brazil strain infected, 3 G strain infected, 2 IFN-gamma KO control, 2 IFN-gamma KO infected, 1 NK cell depleted control, 1 NK cell depleted infected, 3 WT (129) control, 3 WT (129) infected, 3 IFNAR KO control, 3 IFNAR KO infected

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The antiviral nuclear body protein SP140 represses Ifnb1 transcript stabilization by the novel regulator RESIST [RNA-seq]

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