A conserved IFN-alpha receptor tyrosine motif directs the biological response to type I IFNs.
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.
Zhao
Wenli
W
Department of Microbiology, Columbia University, New York, NY 10032, USA.
Lee
Carolyn
C
Piganis
Rebecca
R
Plumlee
Courtney
C
de Weerd
Nicole
N
Hertzog
Paul J
PJ
Schindler
Christian
C
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
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