ARAP2 regulates responses to interferon-gamma by restricting SOCS1

Keating, N; Doggett, K; Bidgood, GM; Meza Guzman, LG; Dagley, LF; Li, K; Williams, BE; Gabrielyan, A; Alvarado, C; Broomfield, BJ; Duckworth, BC; Hockings, C; Yousef, J; Leong, E; Morris, R; Kueh, A; Garnham, AL; Giner, G; Casanova, JL; Boisson-Dupuis, S; Babon, JJ; Linossi, EM; Tate, MD; Groom, JR; Nicholson, SE

Author(s): Keating, N; Doggett, K; Bidgood, GM; Meza Guzman, LG; Dagley, LF; Li, K; Williams, BE; Gabrielyan, A; Alvarado, C; Broomfield, BJ; Duckworth, BC; Hockings, C; Yousef, J; Leong, E; Morris, R; Kueh, A; Garnham, AL; Giner, G; Casanova, JL; Boisson-Dupuis, S; Babon, JJ; Linossi, EM; Tate, MD; Groom, JR; Nicholson, SE;
Details: Publication Year 2025-12-15,Volume 44,Issue #12,Page 116667
Journal Title: Cell Reports
Abstract: Interferon-gamma (IFNγ) is critical for immunity against intra-macrophagic pathogens, signaling through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway to induce a tyrosine-phosphorylation cascade that ensures a potent immune response. Excessive JAK-STAT signaling can drive hyperinflammation and autoimmunity; 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, ankyrin repeat and pleckstrin homology domain 2 (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, and this exacerbates inflammation in a mouse model of influenza virus infection.
Publisher: Cell Press
Keywords: Arap2; CP: immunology; Ifnγ; Jak; SH2 domain; Socs1; Stat; influenza; interferon; tyrosine
Research Division(s): Inflammation; Advanced Technology and Biology; Immunology; Structural Biology; Blood Cells and Blood Cancer; Bioinformatics and Computational Biology
PubMed ID: 41401070
Publisher's Version: https://doi.org/10.1016/j.celrep.2025.116667
Open Access at Publisher's Site: https://doi.org/10.1016/j.celrep.2025.116667
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-01-22 09:58:55

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