tetano
Editor, Senior Moderator
Cell Rep
. 2025 Dec 15;44(12):116667.
doi: 10.1016/j.celrep.2025.116667. Online ahead of print. ARAP2 regulates responses to interferon-gamma by restricting SOCS1
Narelle Keating[SUP] 1 [/SUP], Karen Doggett[SUP] 1 [/SUP], Grace M Bidgood[SUP] 1 [/SUP], Lizeth G Meza Guzman[SUP] 1 [/SUP], Laura F Dagley[SUP] 1 [/SUP], Kunlun Li[SUP] 1 [/SUP], Bailey E Williams[SUP] 1 [/SUP], Anna Gabrielyan[SUP] 1 [/SUP], Carolina Alvarado[SUP] 1 [/SUP], Benjamin J Broomfield[SUP] 1 [/SUP], Brigette C Duckworth[SUP] 1 [/SUP], Colin Hockings[SUP] 1 [/SUP], Jumana Yousef[SUP] 1 [/SUP], Evelyn Leong[SUP] 1 [/SUP], Rhiannon Morris[SUP] 1 [/SUP], Andrew Kueh[SUP] 2 [/SUP], Alexandra L Garnham[SUP] 1 [/SUP], Göknur Giner[SUP] 1 [/SUP], Jean-Laurent Casanova[SUP] 3 [/SUP], Stephanie Boisson-Dupuis[SUP] 4 [/SUP], Jeffrey J Babon[SUP] 1 [/SUP], Edmond M Linossi[SUP] 5 [/SUP], Michelle D Tate[SUP] 6 [/SUP], Joanna R Groom[SUP] 1 [/SUP], Sandra E Nicholson[SUP] 7 [/SUP]
Affiliations
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.
Keywords: ARAP2; CP: immunology; IFNγ; JAK; SH2 domain; SOCS1; STAT; influenza; interferon; tyrosine.
. 2025 Dec 15;44(12):116667.
doi: 10.1016/j.celrep.2025.116667. Online ahead of print. ARAP2 regulates responses to interferon-gamma by restricting SOCS1
Narelle Keating[SUP] 1 [/SUP], Karen Doggett[SUP] 1 [/SUP], Grace M Bidgood[SUP] 1 [/SUP], Lizeth G Meza Guzman[SUP] 1 [/SUP], Laura F Dagley[SUP] 1 [/SUP], Kunlun Li[SUP] 1 [/SUP], Bailey E Williams[SUP] 1 [/SUP], Anna Gabrielyan[SUP] 1 [/SUP], Carolina Alvarado[SUP] 1 [/SUP], Benjamin J Broomfield[SUP] 1 [/SUP], Brigette C Duckworth[SUP] 1 [/SUP], Colin Hockings[SUP] 1 [/SUP], Jumana Yousef[SUP] 1 [/SUP], Evelyn Leong[SUP] 1 [/SUP], Rhiannon Morris[SUP] 1 [/SUP], Andrew Kueh[SUP] 2 [/SUP], Alexandra L Garnham[SUP] 1 [/SUP], Göknur Giner[SUP] 1 [/SUP], Jean-Laurent Casanova[SUP] 3 [/SUP], Stephanie Boisson-Dupuis[SUP] 4 [/SUP], Jeffrey J Babon[SUP] 1 [/SUP], Edmond M Linossi[SUP] 5 [/SUP], Michelle D Tate[SUP] 6 [/SUP], Joanna R Groom[SUP] 1 [/SUP], Sandra E Nicholson[SUP] 7 [/SUP]
Affiliations
- PMID: 41401070
- DOI: 10.1016/j.celrep.2025.116667
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.
Keywords: ARAP2; CP: immunology; IFNγ; JAK; SH2 domain; SOCS1; STAT; influenza; interferon; tyrosine.