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: 4.42). 12/2008; 71(2):350 - 368. DOI: 10.1111/j.1365-2958.2008.06524.x
Source: PubMed


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.

Download full-text


Available from: Daniel Vincent Zurawski, Oct 06, 2015
14 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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 · 3.61 Impact Factor
  • Source
    • "While examining the genes within the T3SS2 pathogenicity island (vpa1310–vpa1396) we identified vpa1380 as a putative T3SS2 effector. The vpa1380 gene encodes for a 295 amino acid protein, which is homologous to the partially characterized OspB effector from Shigella flexneri (32% identity and 50% similarity) [19], [20] (Fig. S1). VPA1380 was recently shown to be secreted from V. parahaemolyticus via the T3SS2 [17]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Vibrio parahaemolyticus is a Gram-negative halophilic bacterium and one of the leading causes of food-borne gastroenteritis. Its genome harbors two Type III Secretion Systems (T3SS1 and T3SS2), but only T3SS2 is required for enterotoxicity seen in animal models. Effector proteins secreted from T3SS2 have been previously shown to promote colonization of the intestinal epithelium, invasion of host cells, and destruction of the epithelial monolayer. In this study, we identify VPA1380, a T3SS2 effector protein that is toxic when expressed in yeast. Bioinformatic analyses revealed that VPA1380 is highly similar to the inositol hexakisphosphate (IP6)-inducible cysteine protease domains of several large bacterial toxins. Mutations in conserved catalytic residues and residues in the putative IP6-binding pocket abolished toxicity in yeast. Furthermore, VPA1380 was not toxic in IP6 deficient yeast cells. Therefore, our findings suggest that VPA1380 is a cysteine protease that requires IP6 as an activator.
    PLoS ONE 08/2014; 9(8)(8):e104387. DOI:10.1371/journal.pone.0104387 · 3.23 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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 · 6.84 Impact Factor
Show more