Keating, N.; Doggett, K.; Bidgood, G.; Guzman, L. G. M.; Dagley, L.; Li, K.; Gabrielyan, A.; Alvarado, C.; Williams, B.; Broomfield, B.; Duckworth, B.; Hockings, C.; Youssef, J.; Leong, E.; Morris, R.; Kueh, A.; Garnham, A.; Casanova, J.-L.; Boisson-Dupuis, S.; Babon, J.; Linossi, E.; Tate, M. D.; Groom, J. R.; Nicholson, S.

Interferon-gamma (IFN{gamma}) is critical for immunity against intra-macrophagic pathogens, signaling through the JAK-STAT pathway to induce a tyrosine-phosphorylation cascade that ensures a potent immune response. Excessive JAK-STAT signaling can drive hyperinflammation and autoimmunity, and thus signaling is tightly and selectively regulated by the IFN{gamma}-inducible protein, Suppressor of Cytokine Signaling 1 (SOCS1). SOCS1 inhibits signaling by directly blocking JAK kinase activity. Here we identified a SOCS1-interacting partner, ARAP2 that fine-tunes SOCS1 function. We report that tyrosine 415 in ARAP2 binds the SOCS1-Src Homology 2 (SH2) domain and limits the ability of SOCS1 to inhibit IFN{gamma} signaling. Our findings show that ARAP2 promotes the IFN{gamma} response through a phosphorylation dependent interaction with the negative regulator SOCS1.