Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ-mediated host defenses.
Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ-mediated host defenses.
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DOI：
10.1084/jem.20160340
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发表时间：
2016-08-22
期刊：
影响因子：
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通讯作者：
Hakimi MA
中科院分区：
文献类型：
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作者：
Gay G;Braun L;Brenier-Pinchart MP;Vollaire J;Josserand V;Bertini RL;Varesano A;Touquet B;De Bock PJ;Coute Y;Tardieux I;Bougdour A;Hakimi MA
Gay等人鉴定了一种弓形虫分泌的效应子，其募集NuRD转录抑制因子并阻断IFN-γ刺激的STAT 1依赖性基因表达，从而抑制宿主对感染的反应。弓形虫感染的早期标志是通过强有力的多方面先天免疫应答来快速控制寄生虫群体，所述先天免疫应答使常驻和归巢免疫细胞沿着促炎和抗炎细胞因子。在这种情况下，IFN-γ激活多种T.在免疫和非免疫细胞中的gondii靶向活性，但也可以有助于宿主免疫病理学。T.弓形虫已经进化出通过干扰IFN-γ刺激基因的转录来及时抵消宿主IFN-γ防御的机制。我们现在已经确定了TgIST（T. STAT 1转录活性的弓形虫抑制剂）作为一种关键的分子开关，由细胞内寄生虫分泌并运输到宿主细胞核，在那里它抑制STAT 1依赖性促炎基因表达。我们发现，TgIST不仅螯合STAT 1专用的基因座，但也促进了非允许染色质的形成，通过其能力，招募核小体重塑脱乙酰酶（NuRD）转录抑制因子。我们发现，在小鼠急性感染期间，TgIST缺陷型寄生虫被归巢的Gr 1+炎性单核细胞迅速清除，从而突出了TgIST对IFN-γ介导的杀伤的保护作用。通过揭示TgIST功能，这项研究为T。弓形虫已经发明了一种分子武器，用来控制后生动物中普遍存在的免疫基因表达机制，作为促进长期寄生的一种方式。
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. An early hallmark of Toxoplasma gondii infection is the rapid control of the parasite population by a potent multifaceted innate immune response that engages resident and homing immune cells along with pro- and counter-inflammatory cytokines. In this context, IFN-γ activates a variety of T. gondii–targeting activities in immune and nonimmune cells but can also contribute to host immune pathology. T. gondii has evolved mechanisms to timely counteract the host IFN-γ defenses by interfering with the transcription of IFN-γ–stimulated genes. We now have identified TgIST (T. gondii inhibitor of STAT1 transcriptional activity) as a critical molecular switch that is secreted by intracellular parasites and traffics to the host cell nucleus where it inhibits STAT1-dependent proinflammatory gene expression. We show that TgIST not only sequesters STAT1 on dedicated loci but also promotes shaping of a nonpermissive chromatin through its capacity to recruit the nucleosome remodeling deacetylase (NuRD) transcriptional repressor. We found that during mice acute infection, TgIST-deficient parasites are rapidly eliminated by the homing Gr1+ inflammatory monocytes, thus highlighting the protective role of TgIST against IFN-γ–mediated killing. By uncovering TgIST functions, this study brings novel evidence on how T. gondii has devised a molecular weapon of choice to take control over a ubiquitous immune gene expression mechanism in metazoans, as a way to promote long-term parasitism.