title: A conserved IFN-alpha receptor tyrosine motif directs the biological response to type I IFNs.
abstract: Mammalian type I IFNs (IFN-Is) mediate their potent biological activities through an evolutionarily conserved IFN-alpha receptor (IFNAR), consisting of IFNAR1 and IFNAR2. These two chains direct the rapid activation of two founding members of the STAT family of transcription factors, STAT1 and STAT2. To understand how IFN-Is direct the recruitment and activation of STATs, a series of mutant murine IFNAR1 and IFNAR2 receptors were generated and evaluated in IFNAR1 and IFNAR2 knockout cells. These studies reveal that a single conserved IFNAR2 tyrosine, Y(510), plays a critical role in directing the IFN-I-dependent activation of STAT1 and STAT2, both in murine fibroblasts and macrophages. A second IFNAR2 tyrosine, Y(335), plays a more minor role. Likewise, Y(510) > Y(335) play a critical role in the induction of genes and antiviral activity traditionally associated with IFN-Is.
authors.affiliation: Department of Microbiology, Columbia University, New York, NY 10032, USA.
authors.forename: Wenli
authors.initials: W
authors.lastname: Zhao
authors.forename: Carolyn
authors.initials: C
authors.lastname: Lee
authors.forename: Rebecca
authors.initials: R
authors.lastname: Piganis
authors.forename: Courtney
authors.initials: C
authors.lastname: Plumlee
authors.forename: Nicole
authors.initials: N
authors.lastname: de Weerd
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hertzog
authors.forename: Christian
authors.initials: C
authors.lastname: Schindler
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001483:Base Sequence; D005347:Fibroblasts / Q000378:metabolism; D016898:Interferon-alpha / Q000276:immunology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D053633:Receptor, Interferon alpha-beta / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000276:immunology / Q000378:metabolism*; D050795:STAT2 Transcription Factor / Q000276:immunology / Q000378:metabolism*; D014443:Tyrosine / Q000276:immunology / Q000378:metabolism
chemical_list: C508032:Ifnar1 protein, mouse; C508034:Ifnar2 protein, mouse; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; C494080:Stat1 protein, mouse; C494085:Stat2 protein, mouse; D053633:Receptor, Interferon alpha-beta; D014443:Tyrosine