title: Shigella flexneri type III secretion system effectors OspB and OspF target the nucleus to downregulate the host inflammatory response via interactions with retinoblastoma protein.
abstract: OspF, OspG and IpaH(9.8) 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 Delta ospB 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 Delta ospB 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 Delta ospB and Delta ospF 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.
authors.affiliation: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Zurawski
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mumy
authors.forename: Christina S
authors.initials: CS
authors.lastname: Faherty
authors.forename: Beth A
authors.initials: BA
authors.lastname: McCormick
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Maurelli
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009504:Neutrophils / Q000276:immunology / Q000382:microbiology; D011485:Protein Binding; D016160:Retinoblastoma Protein / Q000276:immunology / Q000378:metabolism*; D017384:Sequence Deletion; D012763:Shigella flexneri / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000472:pathogenicity; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D016209:Interleukin-8; D016160:Retinoblastoma Protein