ARAP2 regulates responses to interferon-gamma by restricting SOCS1
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.
Authors
- Colin Hockings (ORCID: https://orcid.org/0000-0002-0248-0517)
- Göknur Giner (ORCID: https://orcid.org/0000-0001-6832-9820)
- Lizeth G. Meza Guzman (ORCID: https://orcid.org/0000-0003-0524-0444)
- Edmond M. Linossi (ORCID: https://orcid.org/0000-0002-8039-573X)
- Laura F. Dagley (ORCID: https://orcid.org/0000-0003-4171-3712)
- Kunlun Li (ORCID: https://orcid.org/0000-0002-7994-878X)
- Alexandra L. Garnham (ORCID: https://orcid.org/0000-0002-8312-8450)
- Joanna R. Groom (ORCID: https://orcid.org/0000-0001-5251-7835)
- Karen Doggett (ORCID: https://orcid.org/0000-0002-8676-8461)
- Benjamin J. Broomfield (ORCID: https://orcid.org/0000-0002-0474-3915)
- Sandra E. Nicholson (ORCID: https://orcid.org/0000-0002-1314-2134)
- Narelle Keating (ORCID: https://orcid.org/0000-0002-4392-0806)
- Andrew J. Kueh (ORCID: https://orcid.org/0009-0005-9596-1422)
- Bailey E Williams (ORCID: https://orcid.org/0009-0007-9438-0778)
- Evelyn Leong
- Carolina Alvarado
- Jumana M. Yousef (ORCID: https://orcid.org/0000-0002-2364-6299)
- Grace M. Bidgood
- Brigette C. Duckworth (ORCID: https://orcid.org/0000-0002-2134-3542)
- Michelle D. Tate (ORCID: https://orcid.org/0000-0002-0587-5514)
- Stéphanie Boisson‐Dupuis (ORCID: https://orcid.org/0000-0002-7115-116X)
- Jeffrey J. Babon (ORCID: https://orcid.org/0000-0002-5408-6239)
- Rhiannon Morris (ORCID: https://orcid.org/0000-0001-6817-6609)
- Jean-Laurent Casanova (ORCID: https://orcid.org/0000-0002-7782-4169)
- Anna Gabrielyan
Institutions
- Inserm (FR)
- University of California, San Francisco (US)
- Walter and Eliza Hall Institute of Medical Research (AU)
- La Trobe University (AU)
- Hudson Institute of Medical Research (AU)
- Assistance Publique – Hôpitaux de Paris (FR)
- Institut des Maladies Génétiques Imagine (FR)
- Rockefeller University (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-12-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.116667
- Primary Topic
- Cytokine Signaling Pathways and Interactions
- Type
- article
- Field-Weighted Citation Impact
- 0.00