SOCS-1 Binding to Tyrosine 441 of IFN-y receptor subunit 1 contributes to the attenuation of IFN-y signaling in vivo

Suppressor of cytokine signaling (SOCS)-1 is a critical inhibitor of IFN-I? 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 Ifngr1441F, in which a putative SOCS-1 binding site, tyrosine 441 (Y441), on the IFN-I? 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-I? signaling. IFN-I?-induced STAT1 activation is prolonged in Ifngr1441F cells, but not to the extent seen in cells completely lacking SOCS-1, suggesting that SOCS-1 maintains activity to modulate IFN-I? signaling via other mechanisms. Despite this, we show that hypersensitivity to IFN-I? results in enhanced innate tumor protection in Ifngr1441F mice in vivo, and unregulated expression of an IFN-I?-dependent chemokine, monokine-induced by IFN-I?. Collectively, these data indicate that Y441 contributes to the regulation of signaling through IFNGR1 via the recruitment of SOCS-1 to the receptor. Copyright A? 2009 by The American Association of Immunologists, Inc.