Kavli Affiliate: Jean-Laurent Casanova
| Authors: Narelle Keating, Karen Doggett, Grace Bidgood, Lizeth G Meza Guzman, Laura Dagley, Kunlun Li, Anna Gabrielyan, Carolina Alvarado, Bailey Williams, Benjamin Broomfield, Brigette Duckworth, Colin Hockings, Jumana Youssef, Evelyn Leong, Rhiannon Morris, Andrew Kueh, Alexandra Garnham, Jean-Laurent Casanova, Stephanie Boisson-Dupuis, Jeffrey Babon, Edmond Linossi, Michelle D Tate, Joanna R. Groom and Sandra Nicholson
| Summary:
Interferon-gamma (IFNγ) 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 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 show that ARAP2 promotes the IFNγ response through a phosphorylation dependent interaction with the negative regulator SOCS1.