title: Beneficial innate signaling interference for antibacterial responses by a Toll-like receptor-mediated enhancement of the MKP-IRF3 axis.
abstract: A major function of innate immune receptors is to recognize pathogen-associated molecular patterns and then evoke immune responses appropriate to the nature of the invading pathogen(s). Because innate immune cells express various types of these receptors, distinct combinations of signaling pathways are activated in response to a given pathogen. Although the conventional wisdom is that these signaling pathways cooperate with one another to ensure an effective host response, a more nuanced view recognizes antagonism between the individual pathways, where the attenuation of a signaling pathway(s) by others may shape the immune response. In this study, we show that, on Listeria monocytogenes infection, Toll-like receptor-triggered MyD88 signaling pathways suppress type I IFN gene induction, which is detrimental to macrophage bactericidal activity. These pathways target and suppress the IFN regulatory factor 3 (IRF3) transcription factor that is activated by the stimulator of IFN genes-TANK-binding kinase-1 kinase pathway. We also provide evidence for the involvement of the MAPK phosphatase family members, which renders IRF3 hypophosphorylated on Toll-like receptor signaling by enhancing the formation of an MAPK phosphatase-IRF3-TANK-binding kinase-1 ternary complex. This study, therefore, reveals a hitherto unrecognized and important contribution of a beneficial innate signaling interference against bacterial infections.
authors.affiliation: Department of Molecular Immunology, Institute of Industrial Science, University of Tokyo, Tokyo 153-8505, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Negishi
authors.forename: Kosuke
authors.initials: K
authors.lastname: Matsuki
authors.forename: Nobuyasu
authors.initials: N
authors.lastname: Endo
authors.forename: Hana
authors.initials: H
authors.lastname: Sarashina
authors.forename: Shoji
authors.initials: S
authors.lastname: Miki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Matsuda
authors.forename: Keiko
authors.initials: K
authors.lastname: Fukazawa
authors.forename: Naoko
authors.initials: N
authors.lastname: Taguchi-Atarashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ikushima
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yanai
authors.forename: Junko
authors.initials: J
authors.lastname: Nishio
authors.forename: Kenya
authors.initials: K
authors.lastname: Honda
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Fujioka
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohba
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.forename: Shun'ichiro
authors.initials: S
authors.lastname: Taniguchi
authors.forename: Eisuke
authors.initials: E
authors.lastname: Nishida
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chi
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Tadatsugu
authors.initials: T
authors.lastname: Taniguchi
mesh_terms: D000818:Animals; D003114:Colony-Forming Units Assay; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology*; D015151:Immunoblotting; D047468:Immunoprecipitation; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D007370:Interferon Type I / Q000037:antagonists & inhibitors; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000276:immunology* / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D046912:Multiprotein Complexes; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D054638:Dual Specificity Phosphatase 1
keywords: host defense; innate immune response; signaling cross-talk