The Orphan Nuclear Receptor TLX Is an Enhancer of STAT1-Mediated Transcription and Immunity to Toxoplasma gondii

Beiting, Daniel P.; Hidano, Shinya; Baggs, Julie E.; Geskes, Jeanne M.; Fang, Qun; Wherry, E. John; Hunter, Christopher A.; Roos, David S.; Cherry, Sara

doi:10.1371/journal.pbio.1002200

Cited by 26 publications

(22 citation statements)

References 82 publications

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“…Finally, the presence of a large and highly altered STAT1 complex on the chromatin may displace normal co-activators such as CBP/p300 and BRG1 that are important for activation (Ni et al, 2005; Ramana et al, 2000). It is interesting to note that inhibition of STAT1 by T. gondii infection can be reversed by over-expression of some co-activators, including the recently described orphan nuclear receptor TLX (Beiting et al, 2015). As such, it may be possible to reverse the action of TgIST by disrupting its interaction with either STAT1 or Mi-2/NuRD or by augmenting other activating factors such as p300/CBP (Zhang et al, 2005) and other histone modifiers (e.g., PARP9-DTX3L ubiquitin ligase) that increase ISG expression (Zhang et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Toxoplasma Effector Recruits the Mi-2/NuRD Complex to Repress STAT1 Transcription and Block IFN-γ-Dependent Gene Expression

Olias

Etheridge

Zhang

et al. 2016

Cell Host & Microbe

167

223

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Summary Interferon gamma (IFN-γ) is an essential mediator of host defense against intracellular pathogens, including the protozoan parasite Toxoplasma gondii. However, prior T. gondii infection blocks IFN-γ-dependent gene transcription, despite the downstream transcriptional activator STAT1 being activated and bound to cognate nuclear promoters. We identify the parasite effector that blocks STAT1-dependent transcription and show it is associated with recruitment of the Mi-2 Nucleosome Remodeling and Deacetylase (NuRD) complex, a chromatin-modifying repressor. This secreted effector, Toxoplasma Inhibitor of STAT1-dependent Transcription (TgIST), translocates to the host cell nucleus where it recruits Mi-2/NuRD to STAT1-dependent promoters, resulting in altered chromatin and blocked transcription. TgIST is conserved across strains, underlying their shared ability to block IFN-γ-dependent transcription. TgIST deletion results in increased parasite clearance in IFN-γ-activated cells and reduced mouse virulence, which is restored in IFN-γ-receptor deficient mice. These findings demonstrate the importance of both IFN-γ responses and the ability of pathogens to counteract these defenses.

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Section: Discussionmentioning

confidence: 99%

Toxoplasma Effector Recruits the Mi-2/NuRD Complex to Repress STAT1 Transcription and Block IFN-γ-Dependent Gene Expression

Olias

Etheridge

Zhang

et al. 2016

Cell Host & Microbe

167

223

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“…Microarrays and data analyses were performed as previously described (Beiting et al, 2015). Briefly, total RNA was isolated from sorted BMMøs using the Qiagen RNeasy kit.…”

Section: Methodsmentioning

confidence: 99%

The Toxoplasma gondii virulence factor ROP16 acts in cis and trans, and suppresses T cell responses

Chen

Christian

Kochanowsky

et al. 2020

Journal of Experimental Medicine

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The ability of Toxoplasma gondii to inject the rhoptry kinase ROP16 into host cells results in the activation of the transcription factors STAT3 and STAT6, but it is unclear how these events impact infection. Here, parasites that inject Cre-recombinase with rhoptry proteins were used to distinguish infected macrophages from those only injected with parasite proteins. Transcriptional profiling revealed that injection of rhoptry proteins alone was sufficient to induce an M2 phenotype that is dependent on STAT3 and STAT6, but only infected cells displayed reduced expression of genes associated with antimicrobial activity and protective immunity. In vivo, the absence of STAT3 or STAT6 improved parasite control, while the loss of ROP16 resulted in a marked reduction in parasite numbers and heightened parasite-specific T cell responses. Thus, ROP16 is a virulence factor that can act in cis and trans to promote M2 programs and which limits the magnitude of parasite-specific T cell responses.

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“…Data analysis was carried out using the statistical computing environment R, the Bioconductor suite of packages for R, and RStudio (57). Raw data were background-subtracted, variancestabilized, and normalized by robust spline normalization.…”

Section: Sequencing Data Analysismentioning

confidence: 99%

Lysophospholipids induce innate immune transdifferentiation of endothelial cells, resulting in prolonged endothelial activation

Wang

et al. 2018

Journal of Biological Chemistry

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Innate immune cells express danger-associated molecular pattern (DAMP) receptors, T-cell costimulation/coinhibition receptors, and major histocompatibility complex II (MHC-II). We have recently proposed that endothelial cells can serve as innate immune cells, but the molecular mechanisms involved still await discovery. Here, we investigated whether human aortic endothelial cells (HAECs) could be transdifferentiated into innate immune cells by exposing them to hyperlipidemia-up-regulated DAMP molecules, lysophospholipids. Performing RNA-seq analysis of lysophospholipid-treated HAECs, we found that lysophosphatidylcholine (LPC) and lysophosphatidylinositol (LPI) regulate largely distinct gene programs as revealed by principal component analysis. Metabolically, LPC up-regulated genes that are involved in cholesterol biosynthesis, presumably through sterol regulatory element-binding protein 2 (SREBP2). By contrast, LPI up-regulated gene transcripts critical for the metabolism of glucose, lipids, and amino acids. Of note, we found that LPC and LPI both induce adhesion molecules, cytokines, and chemokines, which are all classic markers of endothelial cell activation, in HAECs. Moreover, LPC and LPI shared the ability to transdifferentiate HAECs into innate immune cells, including induction of potent DAMP receptors, such as CD36 molecule, T-cell costimulation/coinhibition receptors, and MHC-II proteins. The induction of these innate-immunity signatures by lysophospholipids correlated with their ability to induce up-regulation of cytosolic calcium and mitochondrial reactive oxygen species. In conclusion, lysophospholipids such as LPC and LPI induce innate immune cell transdifferentiation in HAECs. The concept of prolonged endothelial activation, discovered here, is relevant for designing new strategies for managing cardiovascular diseases.

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The Orphan Nuclear Receptor TLX Is an Enhancer of STAT1-Mediated Transcription and Immunity to Toxoplasma gondii

Cited by 26 publications

References 82 publications

Toxoplasma Effector Recruits the Mi-2/NuRD Complex to Repress STAT1 Transcription and Block IFN-γ-Dependent Gene Expression

Toxoplasma Effector Recruits the Mi-2/NuRD Complex to Repress STAT1 Transcription and Block IFN-γ-Dependent Gene Expression

The Toxoplasma gondii virulence factor ROP16 acts in cis and trans, and suppresses T cell responses

Lysophospholipids induce innate immune transdifferentiation of endothelial cells, resulting in prolonged endothelial activation

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