SOCS-1 binding to tyrosine 441 of IFN-gamma receptor subunit 1 contributes to the attenuation of IFN-gamma signaling in vivo.
Suppressor of cytokine signaling (SOCS)-1 is a critical inhibitor of IFN-gamma 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-gamma 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-gamma signaling. IFN-gamma-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-gamma signaling via other mechanisms. Despite this, we show that hypersensitivity to IFN-gamma results in enhanced innate tumor protection in Ifngr1(441F) mice in vivo, and unregulated expression of an IFN-gamma-dependent chemokine, monokine-induced by IFN-gamma. Collectively, these data indicate that Y441 contributes to the regulation of signaling through IFNGR1 via the recruitment of SOCS-1 to the receptor.
Starr
Robyn
R
Signal Transduction Laboratory, St Vincent's Institute, 9 Princes Street, Fitzroy, Victoria 3065, Australia. rstarr@svi.edu.au
Fuchsberger
Martina
M
Lau
Lei Shong
LS
Uldrich
Adam P
AP
Goradia
Ankita
A
Willson
Tracy A
TA
Verhagen
Anne M
AM
Alexander
Warren S
WS
Smyth
Mark J
MJ
D000818:Animals; D002478:Cells, Cultured; D055879:Gene Knock-In Techniques; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000556:secondary; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*; D000096743:Interferon gamma Receptor
D007371:Interferon-gamma; D021122:Protein Subunits; D017471:Receptors, Interferon; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014443:Tyrosine; D000096743:Interferon gamma Receptor; C491590:Socs1 protein, mouse