title: Structural basis of a unique interferon-β signaling axis mediated via the receptor IFNAR1.
abstract: Type I interferons are important in regulating immune responses to pathogens and tumors. All interferons are considered to signal via the heterodimeric IFNAR1-IFNAR2 complex, yet some subtypes such as interferon-β (IFN-β) can exhibit distinct functional properties, although the molecular basis of this is unclear. Here we demonstrate IFN-β can uniquely and specifically ligate to IFNAR1 in an IFNAR2-independent manner, and we provide the structural basis of the IFNAR1-IFN-β interaction. The IFNAR1-IFN-β complex transduced signals that modulated expression of a distinct set of genes independently of Jak-STAT pathways. Lipopolysaccharide-induced sepsis was ameliorated in Ifnar1(-/-) mice but not Ifnar2(-/-) mice, suggesting that IFNAR1-IFN-β signaling is pathologically relevant. Thus, we provide a molecular basis for understanding specific functions of IFN-β.
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: de Weerd
authors.forename: Julian P
authors.initials: JP
authors.lastname: Vivian
authors.forename: Thao K
authors.initials: TK
authors.lastname: Nguyen
authors.forename: Niamh E
authors.initials: NE
authors.lastname: Mangan
authors.forename: Jodee A
authors.initials: JA
authors.lastname: Gould
authors.forename: Susie-Jane
authors.initials: SJ
authors.lastname: Braniff
authors.forename: Leyla
authors.initials: L
authors.lastname: Zaker-Tabrizi
authors.forename: Ka Yee
authors.initials: KY
authors.lastname: Fung
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Forster
authors.forename: Travis
authors.initials: T
authors.lastname: Beddoe
authors.forename: Hugh H
authors.initials: HH
authors.lastname: Reid
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hertzog
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D016899:Interferon-beta / Q000737:chemistry* / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000009:adverse effects; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D055550:Protein Stability; D053633:Receptor, Interferon alpha-beta / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012772:Shock, Septic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D015398:Signal Transduction
chemical_list: D008070:Lipopolysaccharides; D046912:Multiprotein Complexes; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta