Stabilization of ATF5 by TAK1-Nemo-like kinase critically regulates the interleukin-1ß-stimulated C/EBP signaling pathway.
Mol Cell Biol
; 35(5): 778-88, 2015 Mar.
Article
em En
| MEDLINE
| ID: mdl-25512613
ABSTRACT
Interleukin-1ß (IL-1ß) is a key proinflammatory cytokine that initiates several signaling cascades, including those involving CCAAT/enhancer binding proteins (C/EBPs). The mechanism by which IL-1ß propagates a signal that activates C/EBP has remained elusive. Nemo-like kinase (NLK) is a mitogen-activated protein kinase (MAPK)-like kinase associated with many pathways and phenotypes that are not yet well understood. Using a luciferase reporter screen, we found that IL-1ß-induced C/EBP activation was positively regulated by NLK. Overexpression of NLK activated C/EBP and potentiated IL-1ß-triggered C/EBP activation, whereas knockdown or knockout of NLK had the opposite effect. NLK interacted with activating transcription factor 5 (ATF5) and inhibited the proteasome-dependent degradation of ATF5 in a kinase-independent manner. Consistently, NLK deficiency resulted in decreased levels of ATF5. NLK cooperated with ATF5 to activate C/EBP, whereas NLK could not activate C/EBP upon knockdown of ATF5. Moreover, TAK1, a downstream effector of IL-1ß that acts upstream of NLK, mimicked the ability of NLK to stabilize ATF5 and activate C/EBP. Thus, our findings reveal the TAK1-NLK pathway as a novel regulator of basal or IL-1ß-triggered C/EBP activation though stabilization of ATF5.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Regulação Enzimológica da Expressão Gênica
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Proteínas Serina-Treonina Quinases
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MAP Quinase Quinase Quinases
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Proteínas Estimuladoras de Ligação a CCAAT
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Peptídeos e Proteínas de Sinalização Intracelular
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Fatores Ativadores da Transcrição
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Interleucina-1beta
Limite:
Animals
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Humans
Idioma:
En
Revista:
Mol Cell Biol
Ano de publicação:
2015
Tipo de documento:
Article