ARAP2 regulates responses to interferon-gamma by restricting SOCS1

Narelle Keating; Karen Doggett; Grace M. Bidgood; Lizeth G. Meza Guzman; Laura F. Dagley; Kunlun Li; Bailey E. Williams; Anna Gabrielyan; Carolina Alvarado; Benjamin J. Broomfield; Brigette C. Duckworth; Colin Hockings; Jumana M. Yousef; Evelyn Leong; Rhiannon Morris; Andrew J. Kueh; Alexandra L. Garnham; Göknur Giner; Jean‐Laurent Casanova; Stéphanie Boisson‐Dupuis; Jeffrey J. Babon; Edmond M. Linossi; Michelle D. Tate; Joanna R. Groom; Sandra E. Nicholson

doi:10.1016/j.celrep.2025.116667

Cell BiologyCell ReportsDec 1, 2025

Peer-reviewed journal article

ARAP2 regulates responses to interferon-gamma by restricting SOCS1

Narelle Keating iD, Karen Doggett iD, Grace M. Bidgood iD, Lizeth G. Meza Guzman iD, Laura F. Dagley iD, Kunlun Li iD, Bailey E. Williams iD, Anna Gabrielyan, Carolina Alvarado iD, Benjamin J. Broomfield iD, Brigette C. Duckworth iD, Colin Hockings iD, Jumana M. Yousef iD, Evelyn Leong, Rhiannon Morris iD, Andrew J. Kueh iD, Alexandra L. Garnham iD, Göknur Giner iD, Jean‐Laurent Casanova iD, Stéphanie Boisson‐Dupuis iD, Jeffrey J. Babon iD, Edmond M. Linossi iD, Michelle D. Tate iD, Joanna R. Groom iD, Sandra E. Nicholson iD

Abstract

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.

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