ASK1 inhibits interleukin-1-induced NF-kappa B activity through disruption of TRAF6-TAK1 interaction.
Apoptosis signal-regulating kinase 1 (ASK1) is a member of the MAPKKK family in the JNK and p38 mitogen-activated protein kinase cascades and critically involved in stress- and cytokine-induced apoptosis. The transcription factor nuclear factor-kappaB (NF-kappaB) is a pivotal regulator of immune and inflammatory responses and exerts anti-apoptotic roles in various cells. Here we show that ASK1 directly interacts with transforming growth factor-beta-activated kinase 1 (TAK1), another MAPKKK that has been identified as a signaling intermediate in the interleukin 1 (IL-1)-induced NF-kappaB pathway as well as the transforming growth factor-beta superfamily-induced JNK/p38 pathway. Overexpression of ASK1 inhibits IL-1-, TRAF6-, or TAK1-induced, but not NF-kappaB-inducing kinase-induced, NF-kappaB activation. ASK1 dissociates TAK1 but not NF-kappaB-inducing kinase from TRAF6. Moreover, IL-1-induced complex formation of endogenous TAK1 and TRAF6 was blocked by ASK1 overexpression. It thus appears that the inhibition of NF-kappaB by ASK1 may result at least in part from the disruption of the TRAF6.TAK1 complex formation in the IL-1 signaling pathway. These results provide a new insight in the mode of action of MAPKKK family members; two distinct MAPKKKs in the same MAP kinase cascades directly interact and exert opposite effects in another signaling pathway, NF-kappaB.
Laboratory of Cell Signaling, Department of Hard Tissue Engineering, Division of Bio-Matrix, Tokyo, Japan.
Y
Y
Mochida
K
K
Takeda
M
M
Saitoh
H
H
Nishitoh
T
T
Amagasa
J
J
Ninomiya-Tsuji
K
K
Matsumoto
H
H
Ichijo
D002460:Cell Line; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology* / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000502:physiology*; D053573:Receptors, Interleukin-1 Type I; D011994:Recombinant Proteins / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology; D048029:TNF Receptor-Associated Factor 6; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7
D007375:Interleukin-1; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D011506:Proteins; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D011994:Recombinant Proteins; D048029:TNF Receptor-Associated Factor 6; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C482858:MAP3K5 protein, human