ARAP2 regulates the Interferon-gamma response by restricting SOCS1

Interferon-gamma (IFNγ) is a critical cytokine required to coordinate anti-viral immunity in response to pathogens such as influenza. IFNγ signals through the JAK-STAT pathway, inducing a tyrosine-phosphorylation cascade that ensures a potent immune response. Aberrant JAK-STAT signaling can drive hyperinflammation and autoimmunity, and thus signaling is tightly and selectively regulated by the IFNγ-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 IFNγ signaling. Our findings reveal ARAP2 as a key player in influenza immunity that promotes the IFNγ response through a phosphorylation dependent interaction with the negative regulator SOCS1.