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ARAP2 regulates responses to interferon-gamma by restricting SOCS1
Narelle Keating1, Karen Doggett1, Grace M Bidgood1
1Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia.
Cell Reports
|December 16, 2025
Summary
Ankyrin repeat and pleckstrin homology domain 2 (ARAP2) fine-tunes the immune response by interacting with suppressor of cytokine signaling 1 (SOCS1). This interaction promotes interferon-gamma (IFNγ) signaling, potentially exacerbating inflammation.
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- Interferon-gamma (IFNγ) is crucial for immunity against intracellular pathogens, activating the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway.
- Aberrant JAK-STAT signaling contributes to hyperinflammation and autoimmune diseases.
- Suppressor of cytokine signaling 1 (SOCS1) is a key negative regulator of IFNγ signaling, inhibiting JAK kinase activity.
Purpose of the Study:
- To identify novel regulators of SOCS1 function in IFNγ signaling.
- To elucidate the molecular mechanism by which ARAP2 interacts with SOCS1.
- To investigate the role of the ARAP2-SOCS1 interaction in immune responses and inflammation.
Main Methods:
- Co-immunoprecipitation assays to identify SOCS1-interacting proteins.
- Site-directed mutagenesis to map the ARAP2 binding site on SOCS1.
- Western blotting to assess tyrosine phosphorylation levels in the JAK-STAT pathway.
- In vivo studies using a mouse model of influenza virus infection.
Main Results:
- Ankyrin repeat and pleckstrin homology domain 2 (ARAP2) was identified as a novel SOCS1-interacting partner.
- Tyrosine 415 in ARAP2 directly binds to the Src homology 2 (SH2) domain of SOCS1.
- This interaction limits SOCS1's inhibitory effect on IFNγ signaling, thereby promoting the IFNγ response.
- ARAP2-mediated promotion of IFNγ signaling exacerbated inflammation in a mouse model of influenza.
Conclusions:
- ARAP2 fine-tunes SOCS1 function through a phosphorylation-dependent interaction.
- ARAP2 acts as a positive modulator of IFNγ signaling by antagonizing SOCS1.
- The ARAP2-SOCS1 axis represents a potential therapeutic target for inflammatory conditions.
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