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Cited by 1Cytokine Signaling Pathways and Interactionsinterferon and immune responsesProtein Tyrosine Phosphatases

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ARAP2 regulates responses to interferon-gamma by restricting SOCS1

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Keating, Narelle, Doggett, Karen, Bidgood, Grace M., Meza Guzman, Lizeth G., Dagley, Laura F., Li, Kunlun, Williams, Bailey E., Gabrielyan, Anna, Alvarado, Carolina, Broomfield, Benjamin J., Duckworth, Brigette C., Hockings, Colin, Yousef, Jumana, Leong, Evelyn, Morris, Rhiannon, Kueh, Andrew, Garnham, Alexandra L., Giner, Göknur, Casanova, Jean-Laurent, Boisson-Dupuis, Stephanie, Babon, Jeffrey J., Linossi, Edmond M., Tate, Michelle D., Groom, Joanna R., Nicholson, Sandra E.·2025·Cell Reports
DOI 10.1016/j.celrep.2025.116667

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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.

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Metadata

Authors
Keating, N., Doggett, K., Bidgood, G. M., Meza Guzman, L. G., Dagley, L. F., Li, K., Williams, B. E., Gabrielyan, A., Alvarado, C., Broomfield, B. J., Duckworth, B. C., Hockings, C., Yousef, J., Leong, E., Morris, R., Kueh, A., Garnham, A. L., Giner, G., Casanova, J.-L., Boisson-Dupuis, S., Babon, J. J., Linossi, E. M., Tate, M. D., Groom, J. R., & Nicholson, S. E.
Affiliations
  • The University of Melbourne (AU)
  • Hôpital Necker-Enfants Malades (FR)
  • University of California, San Francisco (US)
  • Hudson Institute of Medical Research (AU)
Corresponding author
Nicholson, Sandra E.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2025-12
Volume
44
Issue
12
Pages
116667
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2025.116667
OpenAlex
W4417312873
Cited by
1
References
4
Citations by year
2026: 1
FWCI
0.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc-nd)
Funders
  • National Health and Medical Research Council (1121755, 2011761)
  • State Government of Victoria
  • Fulbright Association
  • University of Melbourne (GNT2007812)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords
SOCS1, interferon-gamma signaling, JAK/STAT signaling, tyrosine phosphorylation, negative regulation of cytokine signaling, influenza, inflammation, macrophages, autoimmunity
MeSH terms
Suppressor of Cytokine Signaling 1 Protein, Animals, Humans, Interferon-gamma, Mice, Inbred C57BL, Orthomyxoviridae Infections, Phosphorylation, Protein Binding, Signal Transduction, src Homology Domains, Adaptor Proteins, Signal Transducing, Mice, HEK293 Cells

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