Suppressor of cytokine Signaling-3 inhibits interleukin-1 signaling by targeting the TRAF-6/TAK1 complex.

Helle Frobøse; Sif Groth Rønn; Peter E Heding; Heidi Mendoza; Philip Cohen; Thomas Mandrup-Poulsen; Nils Billestrup

doi:10.1210/me.2005-0301

Suppressor of cytokine Signaling-3 inhibits interleukin-1 signaling by targeting the TRAF-6/TAK1 complex.

Helle Frobøse, Sif Groth Rønn, Peter E Heding, Heidi Mendoza, Philip Cohen, Thomas Mandrup-Poulsen, Nils Billestrup

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

145 Citationer (Scopus)

Abstract

Udgivelsesdato: 2006-Jul

Originalsprog	Engelsk
Tidsskrift	Molecular Endocrinology
Vol/bind	20
Udgave nummer	7
Sider (fra-til)	1587-96
Antal sider	9
ISSN	0888-8809
DOI	https://doi.org/10.1210/me.2005-0301
Status	Udgivet - 2006

Bibliografisk note

Keywords: Cells, Cultured; Extracellular Signal-Regulated MAP Kinases; Gene Dosage; Humans; Interleukin-1; MAP Kinase Kinase Kinases; Multiprotein Complexes; Nitric Oxide Synthase Type II; Phosphorylation; Protein Binding; Signal Transduction; Suppressor of Cytokine Signaling Proteins; TNF Receptor-Associated Factor 6; Ubiquitin

Adgang til dokumentet

10.1210/me.2005-0301

Citationsformater

Suppressor of cytokine Signaling-3 inhibits interleukin-1 signaling by targeting the TRAF-6/TAK1 complex. / Frobøse, Helle; Rønn, Sif Groth; Heding, Peter E; Mendoza, Heidi; Cohen, Philip; Mandrup-Poulsen, Thomas; Billestrup, Nils.

I: Molecular Endocrinology, Bind 20, Nr. 7, 2006, s. 1587-96.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

@article{3f457890acd211ddb538000ea68e967b,

title = "Suppressor of cytokine Signaling-3 inhibits interleukin-1 signaling by targeting the TRAF-6/TAK1 complex.",

abstract = "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.",

author = "Helle Frob{\o}se and R{\o}nn, {Sif Groth} and Heding, {Peter E} and Heidi Mendoza and Philip Cohen and Thomas Mandrup-Poulsen and Nils Billestrup",

note = "Keywords: Cells, Cultured; Extracellular Signal-Regulated MAP Kinases; Gene Dosage; Humans; Interleukin-1; MAP Kinase Kinase Kinases; Multiprotein Complexes; Nitric Oxide Synthase Type II; Phosphorylation; Protein Binding; Signal Transduction; Suppressor of Cytokine Signaling Proteins; TNF Receptor-Associated Factor 6; Ubiquitin",

year = "2006",

doi = "10.1210/me.2005-0301",

language = "English",

volume = "20",

pages = "1587--96",

journal = "Molecular Endocrinology",

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publisher = "Oxford University Press",

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T1 - Suppressor of cytokine Signaling-3 inhibits interleukin-1 signaling by targeting the TRAF-6/TAK1 complex.

AU - Frobøse, Helle

AU - Rønn, Sif Groth

AU - Heding, Peter E

AU - Mendoza, Heidi

AU - Cohen, Philip

AU - Mandrup-Poulsen, Thomas

AU - Billestrup, Nils

N1 - Keywords: Cells, Cultured; Extracellular Signal-Regulated MAP Kinases; Gene Dosage; Humans; Interleukin-1; MAP Kinase Kinase Kinases; Multiprotein Complexes; Nitric Oxide Synthase Type II; Phosphorylation; Protein Binding; Signal Transduction; Suppressor of Cytokine Signaling Proteins; TNF Receptor-Associated Factor 6; Ubiquitin

PY - 2006

Y1 - 2006

N2 - 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.

AB - 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.

U2 - 10.1210/me.2005-0301

DO - 10.1210/me.2005-0301

M3 - Journal article

C2 - 16543409

VL - 20

SP - 1587

EP - 1596

JO - Molecular Endocrinology

JF - Molecular Endocrinology

SN - 0888-8809

IS - 7

ER -