title: Salmonella Virulence Factor SsrAB Regulated Factor Modulates Inflammatory Responses by Enhancing the Activation of NF-κB Signaling Pathway.
abstract: Effector proteins encoded by Salmonella pathogenicity islands play a key role in promoting bacterial intracellular survival, colonization, and pathogenesis. In this study, we investigated the function of the virulence-associated effector SrfA (SsrAB regulated factor) both in macrophages in vitro and in infected mice in vivo. SrfA was secreted into the cytoplasm during S. Typhimurium infection and disassociated IL-1R-associated kinase-1 (IRAK-1) from the IRAK-1-Toll interacting protein (Tollip) complex by interacting with Tollip. The released IRAK-1 was phosphorylated and subsequently activated the NF-κB signaling pathway, which enhanced the LPS-induced expression of inflammatory cytokines, such as IL-8, IL-1β, and TNF-α. The coupling of ubiquitin to endoplasmic reticulum degradation aa 183-219 domain of Tollip is the binding region for SrfA, and both the MDaa207-226 and CTaa357-377 regions of SrfA mediate binding to Tollip and NF-κB signaling activation. Deletion of SrfA in S. Typhimurium had no notable effects on its replication but impaired the induction of NF-κB activation in infected macrophages. The mice infected with srfA-deficient bacteria exhibited a decreased inflammatory response and an increased survival rate compared with those infected with wild-type S. Typhimurium. We conclude that SrfA is a novel Salmonella virulence effector that helps modulate host inflammatory responses by promoting NF-κB signaling activation.
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China; and.
authors.forename: Lei
authors.initials: L
authors.lastname: Lei
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China; and.
authors.forename: Wenbiao
authors.identifier: http://orcid.org/0000-0003-4944-764X
authors.initials: W
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China; and.
authors.forename: Chuan
authors.initials: C
authors.lastname: Xia
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China; and Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720 fenyongliu@whu.edu.cn.
authors.forename: Fenyong
authors.initials: F
authors.lastname: Liu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D012481:Salmonella Infections, Animal / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D020798:Two-Hybrid System Techniques; D037521:Virulence Factors / Q000276:immunology*
chemical_list: D016328:NF-kappa B; D037521:Virulence Factors