ARAP2 regulates responses to interferon-gamma by restricting SOCS1

Keating, N.; Doggett, K.; Bidgood, G.; Guzman, L. G. M.; Dagley, L.; Li, K.; Gabrielyan, A.; Alvarado, C.; Williams, B.; Broomfield, B.; Duckworth, B.; Hockings, C.; Youssef, J.; Leong, E.; Morris, R.; Kueh, A.; Garnham, A.; Casanova, J.-L.; Boisson-Dupuis, S.; Babon, J.; Linossi, E.; Tate, M. D.; Groom, J. R.; Nicholson, S.

doi:10.1101/2025.04.28.650977

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bioRxiv · 10.1101/2025.04.28.650977

ARAP2 regulates responses to interferon-gamma by restricting SOCS1

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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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Keating, N., Doggett, K., Bidgood, G., Guzman, L. G. M., Dagley, L., Li, K., Gabrielyan, A., Alvarado, C., Williams, B., Broomfield, B., Duckworth, B., Hockings, C., Youssef, J., Leong, E., Morris, R., Kueh, A., Garnham, A., Casanova, J.-L., Boisson-Dupuis, S., Babon, J., Linossi, E., Tate, M. D., Groom, J. R., Nicholson, S.. 2025-04-29. ARAP2 regulates responses to interferon-gamma by restricting SOCS1. https://doi.org/10.1101/2025.04.28.650977

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