Shigella flexneri type III secretion system effectors OspB and OspF target the nucleus to downregulate the host inflammatory response via interactions with retinoblastoma protein

Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA, USA.
Molecular Microbiology (Impact Factor: 5.03). 12/2008; 71(2):350 - 368. DOI: 10.1111/j.1365-2958.2008.06524.x
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ABSTRACT OspF, OspG and IpaH9.8 are type III secretion system (T3SS) effectors of Shigella flexneri that downregulate the host innate immune response. OspF modifies mitogen-activated protein kinase pathways and polymorphonuclear leucocyte transepithelial migration associated with Shigella invasion. OspF also localizes in the nucleus to mediate chromatin remodelling, resulting in reduced transcription of inflammatory cytokines. We now report that OspB can be added to the set of S. flexneri T3SS effectors required to modulate the innate immune response. T84 cells infected with a ΔospB mutant resulted in reduced polymorphonuclear leucocyte transepithelial migration and mitogen-activated protein kinase signalling. Tagged versions of OspB localized with endosomes and the nucleus. Further, T84 cells infected with the ΔospB mutant showed increased levels of secreted IL-8 compared with wild-type infected cells. Both GST–OspB and GST–OspF coprecipitated retinoblastoma protein from host cell lysates. Because ΔospB and ΔospF mutants share similar phenotypes, and OspB and OspF share a host binding partner, we propose that OspB and OspF facilitate the remodelling of chromatin via interactions with retinoblastoma protein, resulting in diminished inflammatory cytokine production. The requirement of multiple T3SS effectors to modulate the innate immune response correlates to the complexity of the human immune system.

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Available from: Daniel Vincent Zurawski, Aug 13, 2015
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    • "Although much progress has been made recently in the molecular and biochemical characterization of these T3SS effectors (Marteyn et al., 2012; Carayol and Tran Van Nhieu, 2013), a defined role for the OspB effector in S. flexneri pathogenesis has not been elucidated yet. Along with VirA, OspF, and OspC1, OspB belongs to the middle effectors and it was shown to be involved in the modulation of the innate immune response (Santapaola et al., 2002; Zurawski et al., 2009). More specifically, it has been suggested that OspB may play a dual role depending on the stage of infection. "
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    ABSTRACT: Through the action of the type three secretion system (T3SS) Shigella flexneri delivers several effectors into host cells to promote cellular invasion, multiplication and to exploit host-cell signaling pathways to modulate the host innate immune response. Although much progress has been made in the understanding of many type III effectors, the molecular and cellular mechanism of the OspB effector is still poorly characterized. In this study we present new evidence that better elucidates the role of OspB as pro-inflammatory factor at very early stages of infection. Indeed, we demonstrate that, during the first hour of infection, OspB is required for full activation of ERK1/2 and p38 MAPKs and the cytosolic phospholipase A2 (cPLA2). Activation of cPLA2 ultimately leads to the production and secretion of PMN chemoattractant metabolite(s) uncoupled with release of IL-8. Moreover, we also present evidence that OspB is required for the development of the full and promptly inflammatory reaction characteristic of S. flexneri wild-type infection in vivo. Based on OspB and OspF similarity (both effectors share similar transcription regulation, temporal secretion into host cells and nuclear localization) we hypothesized that OspB and OspF effectors may form a pair aimed at modulating the host cell response throughout the infection process, with opposite effects. A model is presented to illustrate how OspB activity would promote S. flexneri invasion and bacterial dissemination at early critical phases of infection.
    International Journal of Medical Microbiology 11/2014; 305(1). DOI:10.1016/j.ijmm.2014.11.004 · 3.42 Impact Factor
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    • "De-La-Peña et al., 2012). Pathogens can manipulate histone modifications in host cells to facilitate their infection , supporting a role of these modifications in plant immunity (Anand et al., 2007; Terakura et al., 2007; Zurawski et al., 2009). Mutations in genes coding for histone modification enzymes have been found to alter disease resistance. "
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    ABSTRACT: Disease resistance (R) genes are key components in plant immunity. Here we show that Arabidopsis E3 ubiquitin ligase genes HUB1 (HISTONE MONOUBIQUITINATION1) and HUB2 regulate the expression of the R genes SNC1 (SUPPRESSOR OF npr1-1, CONSTITUTIVE1)and RPP4 (RESISTANCE TO PERONOSPORA PARASITICA 4). An increase of SNC1 expression induces constitutive immune responses in the bon1 (bonzai1) mutant, and the loss of HUB1 or HUB2 function reduces SNC1 upregulation and suppresses the bon1 autoimmune phenotypes. HUB1 and HUB2 mediate H2B monoubiquitination directly at the SNC1 R gene locus to regulate its expression. In addition, SNC1 and HUB1 transcripts are moderately up-regulated by pathogen infection and H2B monoubiquitination at SNC1 is enhanced by pathogen infection. Together, this study indicates that H2B monoubiquitination at the R gene locus regulates its expression and this histone modification at the R gene locus has an impact on immune responses in plants.
    Plant physiology 03/2014; 165(1). DOI:10.1104/pp.113.227801 · 7.39 Impact Factor
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    • "Ma et al. related genes (Arbibe et al., 2007). This function is accomplished through the interaction of OspF with host retinoblastoma protein, which has been linked to histone modification (Zurawski et al., 2009; Fig. 3A). OspF also has the phospho-Thr lyase activity that targets the phosphorylated MAPKs in the nucleus (Li et al., 2007). "
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    ABSTRACT: Regulation of chromatin dynamics by remodeling complexes is well known to play critical roles in gene expression changes during plant development and stress response. Recent discoveries implicated that chromatin remodelers also regulate plant immunity. Upon pathogen infection, histone modifying enzymes and ATP-dependent chromatin remodelers, in conjunction with other regulatory proteins, are recruited to defense-related gene regions, resulting in transcription reprogramming. The presence of a large number of potential components of chromatin remodeling complexes may contribute to the integration of various signals, and eventually lead to the quantitative and kinetical immune response. Biotrophic and hemibiotrophic pathogens have evolved virulence factors to suppress plant defense, which is essential for disease development. The conserved nature of chromatin remodeling complexes makes them attractive targets of these pathogens. Here, we update our knowledge on the emerging role of chromatin configuration in the tight control of plant defense response against bacterial infection, and discuss the potential functions of bacterial virulence proteins to subvert immunity by modulating chromatin-remodeling processes.
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