<i>Toxoplasma gondii</i> TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ–mediated host defenses

Gay, Gabrielle; Braun, Laurence; Brenier-Pinchart, Marie-Pierre; Vollaire, Julien; Josserand, Véronique; Bertini, Rose‐Laurence; Varesano, Aurélie; Touquet, Bastien; Bock, Pieter-Jan De; Couté, Yohann; Tardieux, Isabelle; Bougdour, Alexandre; Hakimi, Mohamed‐Ali

doi:10.1084/jem.20160340

Cited by 182 publications

(258 citation statements)

References 51 publications

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“…Because of the plasmatorrhexis of Mfs caused by tachyzoite proliferation, (41)(42)(43). In addition, ROS inhibits T. gondii activity in mouse monocytes and IFN-g-producing Mfs (44,45). In this study, the ROS levels of Mfs infected with TR-KO or wild-type T. gondii strains were significantly higher than those of uninfected cells.…”

Section: Discussionmentioning

confidence: 53%

Thioredoxin reductase fromToxoplasma gondii: an essential virulence effector with antioxidant function

et al. 2017

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Thioredoxin reductase (TR) can help pathogens resist oxidative-burst injury from host immune cells by maintaining a thioredoxin-reduction state during NADPH consumption. TR is a necessary virulence factor that enables the persistent infection of some parasites. We performed bioinformatics analyses and biochemical assays to characterize the activity, subcellular localization, and genetic ablation of Toxoplasma gondii TR (TgTR), to shed light on its biologic function. We expressed the TgTR protein with an Escherichia coli expression system and analyzed its enzyme activity, reporting a K m for the recombinant TgTR of 11.47-15.57 mM, using NADPH as a substrate, and 130.48-151.09 mM with dithio-bis-nitrobenzoic acid as a substrate. The TgTR sequence shared homology with that of TR, but lacked a selenocysteine residue in the C-terminal region and was thought to contain 2 flavin adenine dinucleotide (FAD) domains and 1 NADPH domain. In addition, immunoelectron microscopy results showed that TgTR was widely dispersed in the cytoplasm, and we observed that parasite antioxidant capacity, invasion efficiency, and proliferation were decreased in TR-knockout (TR-KO) strains in vitro, although this strain still stimulated the release of reactive oxygen species release in mouse macrophages while being more sensitive to H 2 O 2 toxicity in vitro. Furthermore, our in vivo results revealed that the survival time of mice infected with the TR-KO strain was significantly prolonged relative to that of mice infected with the wild-type strain. These results suggest that TgTR plays an important role in resistance to oxidative damage and can be considered a virulence factor associated with T. gondii

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Section: Discussionmentioning

confidence: 53%

Thioredoxin reductase fromToxoplasma gondii: an essential virulence effector with antioxidant function

et al. 2017

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“…Recently, T. gondii was reported to increase the amount of activated STAT1 in the nuclei of infected cells (Gay et al, ; Rosowski et al, ; Rosowski & Saeij, ; Schneider et al, ), whereas earlier studies on this issue yielded different results (Kim et al, ; Lüder et al, ). Therefore, we next determined the levels of STAT1 and its phosphorylated isoforms in cytoplasmic and nuclear fractions of RAW264.7 cells infected or not with T. gondii during stimulation with IFN‐γ.…”

Section: Resultsmentioning

confidence: 99%

“…Phosphorylation of STAT1 at Tyr 701 in response to IFN‐γ is required for nuclear import of STAT1 homodimers in an active conformation, whereas phosphorylation at Ser 727 is necessary for its full transcriptional activity. Conflicting results have been reported on the impact of T. gondii infection on IFN‐γ‐induced STAT1 phosphorylation (Gay et al, ; Kim et al, ; Lüder et al, ; Rosowski & Saeij, ; Schneider et al, ; Zimmermann et al, ). We therefore sought to thoroughly determine levels of total STAT1 and the kinetics of Tyr 701 and Ser 727 phosphorylation in parasite‐infected macrophages.…”

Section: Resultsmentioning

confidence: 99%

“…Efficient control of T. gondii largely relies on interferon‐γ (IFN‐γ; Lykens et al, ; Scharton‐Kersten et al, ; Suzuki, Orellana, Schreiber, & Remington, ) and its downstream mediator signal transducer and activator of transcription‐1 (STAT1; Gavrilescu, Butcher, Del Rio, Taylor, & Denkers, ; Lieberman, Banica, Reiner, & Hunter, ), which upregulate various effector mechanisms in immune and non‐immune cells to control or even to kill the parasite. However, T. gondii partially evades IFN‐γ‐mediated gene expression (Kim, Fouts, & Boothroyd, ; Lang et al, ; Lang, Algner, Beinert, Gross, & Lüder, ; Lüder, Lang et al, ; Lüder, Algner, Lang, Bleicher, & Gross, ; Lüder, Lang, Beuerle, & Gross, ; Lüder, Walter, Beuerle, Maeurer, & Gross, ; Rosowski, Nguyen, Camejo, Spooner, & Saeij, ; Rosowski & Saeij, ; Sumpf, Nast, Downie, Salinas, & Luder, ; Zimmermann, Murray, Heeg, & Dalpke, ) by secreting a parasite effector protein into the host cell where it translocates into the nucleus and recruits the Mi‐2/NuRD repressor complex to STAT1‐responsive promoters (Gay et al, ; Olias, Etheridge, Zhang, Holtzman, & Sibley, ). This effector, called T. gondii inhibitor of STAT1‐dependent transcription (TgIST), is required and does suffice to inhibit IFN‐γ‐dependent gene expression, and TgIST‐deficient parasites are avirulent in mice (Olias et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Toxoplasma gondiistabilises tetrameric complexes of tyrosine-phosphorylated signal transducer and activator of transcription-1 and leads to its sustained and promiscuous DNA binding

Nast

Staab

Meyer

et al. 2018

Cellular Microbiology

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Toxoplasma gondii is an obligate intracellular parasite that infects up to 30% of humans worldwide. It can lead to severe diseases particularly in individuals with immature or defective immune responses. Control of T. gondii relies on the IFN-γ-induced signal transducer and activator of transcription-1 (STAT1) pathway. T. gondii, however, largely inactivates STAT1-mediated gene transcription by T. gondii inhibitor of STAT1-dependent transcription (TgIST), a parasite effector protein binding to STAT1. Here, we have analysed requirements of STAT1 to bind TgIST and characterised downstream effects on STAT1 signalling. TgIST bound to STAT1 dimers but more efficiently assembled with STAT1 tetramers, which are essential for effective IFN-γ responsiveness. Such binding was abrogated in N-terminal, but not C-terminal deletion mutants of STAT1. Furthermore, TgIST did not bind to the STAT1 substitution mutant that cannot form STAT1 tetramers, resulting in a complete unresponsiveness of parasite-infected STAT1 -expressing cells to IFN-γ. Remarkably, binding of TgIST considerably increased the affinity of the aberrant STAT1 tetramers for DNA consensus sequence binding motifs and even enabled binding to nonconsensus sequences. Consistent with the increased DNA binding, STAT1 from parasite-infected cells remained phosphorylated at Tyr and Ser and was retained within the nucleus in a DNA-bound state. The sustained and promiscuous binding activity particularly of STAT1 tetramers to unspecific DNA sites lacking a consensus STAT1-binding motif is an as yet unrecognised mechanism contributing to the defective IFN-γ-mediated signalling in T. gondii-infected cells.

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“…Although STAT1 signaling is activated in response to T. gondii infection in macrophages and other cell types, there are multiple reports that T. gondii modulates this pathway (25–27, 29, 30, 32), but whether this is relevant to astrocytes is unclear. Therefore, in vitro experiments were performed to assess the stimuli that activated STAT1 in primary murine astrocytes and to determine whether this transcription factor was required for their antimicrobial activities.…”

Section: Resultsmentioning

confidence: 99%

STAT1 Signaling in Astrocytes Is Essential for Control of Infection in the Central Nervous System

Hidano

Randall

Dawson

et al. 2016

mBio

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The local production of gamma interferon (IFN-γ) is important to control Toxoplasma gondii in the brain, but the basis for these protective effects is not fully understood. The studies presented here reveal that the ability of IFN-γ to inhibit parasite replication in astrocytes in vitro is dependent on signal transducer and activator of transcription 1 (STAT1) and that mice that specifically lack STAT1 in astrocytes are unable to limit parasite replication in the central nervous system (CNS). This susceptibility is associated with a loss of antimicrobial pathways and increased cyst formation in astrocytes. These results identify a critical role for astrocytes in limiting the replication of an important opportunistic pathogen.

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Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ–mediated host defenses

Abstract: Gay et al. identify a Toxoplasma gondii secreted effector that recruits NuRD transcriptional repressor and blocks IFN-γ–stimulated STAT1-dependent gene expression, thus dampening host responses to infection.

Cited by 182 publications

References 51 publications

Thioredoxin reductase fromToxoplasma gondii: an essential virulence effector with antioxidant function

Thioredoxin reductase fromToxoplasma gondii: an essential virulence effector with antioxidant function

Toxoplasma gondiistabilises tetrameric complexes of tyrosine-phosphorylated signal transducer and activator of transcription-1 and leads to its sustained and promiscuous DNA binding

STAT1 Signaling in Astrocytes Is Essential for Control of Infection in the Central Nervous System

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