Suppressor of cytokine Signaling-3 inhibits interleukin-1 signaling by targeting the TRAF-6/TAK1 complex.
IL-1 plays a major role in inflammation and autoimmunity through activation of nuclear factor kappa B (NFkappaB) and MAPKs. Although a great deal is known about the mechanism of activation of NFkappaB and MAPKs by IL-1, much less is known about the down-regulation of this pathway. Suppressor of cytokine signaling (SOCS)-3 was shown to inhibit IL-1-induced transcription and activation of NFkappaB and the MAPKs JNK and p38, but the mechanism is unknown. We show here that SOCS-3 inhibits NFkappaB-dependent transcription induced by overexpression of the upstream IL-1 signaling molecules MyD88, IL-1R-activated kinase 1, TNF receptor-associated factor (TRAF)6, and TGFbeta-activated kinase (TAK)1, but not when the MAP3K MAPK/ERK kinase kinase-1 is used instead of TAK1, indicating that the target for SOCS-3 is the TRAF6/TAK1 signaling complex. By coimmunoprecipitation, it was shown that SOCS-3 inhibited the association between TRAF6 and TAK1 and that SOCS-3 coimmunoprecipitated with TAK1 and TRAF6. Furthermore, SOCS-3 inhibited the IL-1-induced catalytic activity of TAK1. Because ubiquitination of TRAF6 is required for activation of TAK1, we analyzed the role of SOCS-3 on TRAF6 ubiquitination and found that SOCS-3 inhibited ubiquitin modification of TRAF6. These results indicate that SOCS-3 inhibits IL-1 signal transduction by inhibiting ubiquitination of TRAF6, thus preventing association and activation of TAK1.
Steno Diabetes Center, Niels Steensens Vej 2, 2820 Gentofte, Denmark.
Helle
H
Frobøse
Sif Groth
SG
Rønn
Peter E
PE
Heding
Heidi
H
Mendoza
Philip
P
Cohen
Thomas
T
Mandrup-Poulsen
Nils
N
Billestrup
D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018628:Gene Dosage; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D048049:Extracellular Signal-Regulated MAP Kinases; D007375:Interleukin-1; D020930:MAP Kinase Kinase Kinases; D046912:Multiprotein Complexes; D052247:Nitric Oxide Synthase Type II; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D048029:TNF Receptor-Associated Factor 6; D025801:Ubiquitin; D000099151:MAP Kinase Kinase Kinase 7; C106644:SOCS3 protein, human