title: HSV infection induces production of ROS, which potentiate signaling from pattern recognition receptors: role for S-glutathionylation of TRAF3 and 6.
abstract: The innate immune response constitutes the first line of defense against infections. Pattern recognition receptors recognize pathogen structures and trigger intracellular signaling pathways leading to cytokine and chemokine expression. Reactive oxygen species (ROS) are emerging as an important regulator of some of these pathways. ROS directly interact with signaling components or induce other post-translational modifications such as S-glutathionylation, thereby altering target function. Applying live microscopy, we have demonstrated that herpes simplex virus (HSV) infection induces early production of ROS that are required for the activation of NF-κB and IRF-3 pathways and the production of type I IFNs and ISGs. All the known receptors involved in the recognition of HSV were shown to be dependent on the cellular redox levels for successful signaling. In addition, we provide biochemical evidence suggesting S-glutathionylation of TRAF family proteins to be important. In particular, by performing mutational studies we show that S-glutathionylation of a conserved cysteine residue of TRAF3 and TRAF6 is important for ROS-dependent activation of innate immune pathways. In conclusion, these findings demonstrate that ROS are essential for effective activation of signaling pathways leading to a successful innate immune response against HSV infection.
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Regina
authors.initials: R
authors.lastname: Gonzalez-Dosal
authors.forename: Kristy A
authors.initials: KA
authors.lastname: Horan
authors.forename: Stine H
authors.initials: SH
authors.lastname: Rahbek
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
authors.forename: John J
authors.initials: JJ
authors.lastname: Mieyal
authors.forename: Rune
authors.initials: R
authors.lastname: Hartmann
authors.forename: Søren R
authors.initials: SR
authors.lastname: Paludan
mesh_terms: D000818:Animals; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006561:Herpes Simplex / Q000276:immunology* / Q000378:metabolism*; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051192:Receptors, Pattern Recognition / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D018139:Simplexvirus / Q000276:immunology* / Q000472:pathogenicity; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism
chemical_list: D018925:Chemokines; D016207:Cytokines; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D016328:NF-kappa B; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051192:Receptors, Pattern Recognition; D048008:TNF Receptor-Associated Factor 3; D048029:TNF Receptor-Associated Factor 6; D005978:Glutathione