A positive regulatory role for suppressor of cytokine signaling 1 in IFN-gamma-induced MHC class II expression in fibroblasts.
Suppressor of cytokine signaling 1 (SOCS1) is rapidly induced following stimulation by several cytokines. SOCS1 negatively regulates cytokine receptor signal transduction by inhibiting Janus family tyrosine kinases. Lack of such feedback regulation underlies the premature death of SOCS1(-/-) mice due to unbridled IFN-gamma signaling. We used mouse embryo fibroblasts derived from SOCS1(-/-) mice to investigate the role of SOCS1 in IFN-gamma signaling pathways. SOCS1(-/-) fibroblasts were exquisitely sensitive to the IFN-gamma-mediated growth arrest and showed sustained STAT1 phosphorylation. However, SOCS1(-/-) fibroblasts were inefficient in MHC class II surface expression following IFN-gamma stimulation, despite a marked induction of the MHC class II transactivator and MHC class II gene expression. Retroviral transduction of wild-type SOCS1 relieved the growth-inhibitory effects of IFN-gamma in SOCS1(-/-) fibroblasts by inhibiting STAT1 activation. SOCS1R105K, carrying a mutation within the phosphotyrosine-binding pocket of the Src homology 2 domain, did not inhibit STAT1 phosphorylation, yet considerably inhibited IFN-gamma-mediated growth arrest. Strikingly, expression of SOCS1R105K restored the IFN-gamma-induced MHC class II expression in SOCS1(-/-) cells, indicating that expression of SOCS1 facilitates MHC class II expression in fibroblasts. Our results show that SOCS1, in addition to its negative regulatory role of inhibiting Janus kinases, has an unanticipated positive regulatory function in retarding the degradation of IFN-gamma-induced MHC class II proteins in fibroblasts.
Ilangumaran
Subburaj
S
Ontario Cancer Institute, Toronto, Canada.
Finan
Dina
D
La Rose
José
J
Raine
Jason
J
Silverstein
Anna
A
De Sepulveda
Paulo
P
Rottapel
Robert
R
D016475:3T3 Cells; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology; D005802:Genes, MHC Class II; D006131:Growth Inhibitors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D021381:Protein Transport / Q000276:immunology; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D000949:Histocompatibility Antigens Class II; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D007371:Interferon-gamma