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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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    • "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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    • "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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