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A Conserved IFN- Receptor Tyrosine Motif Directs the Biological Response to Type I IFNs¹

Wenli Zhao^*, Carolyn Lee^*, Rebecca Piganis, Courtney Plumlee^*, Nicole de Weerd, Paul J. Hertzog and Christian Schindler^2,*,

^* Department of Microbiology and Department of Medicine, Columbia University, New York, NY 10032; and Center for Monash Institute for Medical Research, Monash University, Clayton, Australia

Mammalian type I IFNs (IFN-Is) mediate their potent biological activities through an evolutionarily conserved IFN- 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, Y⁵¹⁰, 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, Y³³⁵, plays a more minor role. Likewise, Y⁵¹⁰ > Y³³⁵ play a critical role in the induction of genes and antiviral activity traditionally associated with IFN-Is.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI 058211 (to W.Z., C.L., and C.S.) and 5T32 AI07525 (to C.P.), the National Multiple Sclerosis Society (Award RG 3237), and the Immunology Training Program (5T32 GM 07367 to C.P.).

² Address correspondence and reprint requests to Dr. Christian Schindler, Columbia University, Hammer Health Science Center 1212, 701 West 168th Street, New York, NY 10032. E-mail address: cws4{at}columbia.edu

³ Abbreviations used in this paper: IFN-I, type I IFN; IFNAR, IFN- receptor; SOCS, suppressor of cytokine signaling; ISRE, IFN-I-stimulated response element; GAS, -IFN activation site; MEF, murine embryonic fibroblast; BMM, bone marrow macrophages; VSV, vesicular stomatitis virus; pMIG, MSCV-IRES-GFP; Q-PCR, quantitative-PCR.