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SOCS-1 Binding to Tyrosine 441 of IFN- Receptor Subunit 1 Contributes to the Attenuation of IFN- Signaling In Vivo¹

Robyn Starr^2,*, Martina Fuchsberger^*, Lei Shong Lau^*, Adam P. Uldrich, Ankita Goradia^*, Tracy A. Willson, Anne M. Verhagen^*, Warren S. Alexander and Mark J. Smyth

^* Signal Transduction Laboratory, St Vincent’s Institute, Fitzroy, Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, and Molecular Medicine Division, Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

Suppressor of cytokine signaling (SOCS)-1 is a critical inhibitor of IFN- signal transduction in vivo, but the precise biochemical mechanism of action of SOCS-1 is unclear. Studies in vitro have shown that SOCS-1 binds to Jaks and inhibits their catalytic activity, but recent studies indicate SOCS-1 may act in a similar manner to SOCS-3 by firstly interacting with cytokine receptors and then inhibiting Jak activity. Here, we have generated mice, termed Ifngr1^441F, in which a putative SOCS-1 binding site, tyrosine 441 (Y441), on the IFN- receptor subunit 1 (IFNGR1) is mutated. We confirm that SOCS-1 binds to IFNGR1 in wild-type but not mutant cells. Mutation of Y441 results in impaired negative regulation of IFN- signaling. IFN--induced STAT1 activation is prolonged in Ifngr1^441F cells, but not to the extent seen in cells completely lacking SOCS-1, suggesting that SOCS-1 maintains activity to modulate IFN- signaling via other mechanisms. Despite this, we show that hypersensitivity to IFN- results in enhanced innate tumor protection in Ifngr1^441F mice in vivo, and unregulated expression of an IFN-–dependent chemokine, monokine-induced by IFN-. Collectively, these data indicate that Y441 contributes to the regulation of signaling through IFNGR1 via the recruitment of SOCS-1 to the receptor.

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 Program Grants 461219 and 454569 and Research Fellowships (to W.S.A. and M.J.S.) from the National Health and Medical Research Council of Australia, and a Senior Medical Research Fellowship from the Sylvia and Charles Viertel Foundation (to R.S.).

² Address correspondence and reprint requests to Dr. Robyn Starr, St Vincent’s Institute, 9 Princes Street, Fitzroy, Victoria 3065, Australia. E-mail address: rstarr{at}svi.edu.au

³ Abbreviations used in this paper: IFNGR1, IFN- receptor subunit 1; SOCS, suppressor of cytokine signaling; DP, double positive; GalCer, -galactosylceramide; MIG, monokine-induced by IFN-; wt, wild type.