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Stabilization of ATF5 by TAK1-Nemo-like kinase critically regulates the interleukin-1?-stimulated C/EBP signaling pathway.

ABSTRACT: Interleukin-1? (IL-1?) is a key proinflammatory cytokine that initiates several signaling cascades, including those involving CCAAT/enhancer binding proteins (C/EBPs). The mechanism by which IL-1? 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-1?-induced C/EBP activation was positively regulated by NLK. Overexpression of NLK activated C/EBP and potentiated IL-1?-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-1? 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-1?-triggered C/EBP activation though stabilization of ATF5.

SUBMITTER: Zhang ZY

PROVIDER: S-EPMC4323494 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Stabilization of ATF5 by TAK1-Nemo-like kinase critically regulates the interleukin-1β-stimulated C/EBP signaling pathway.

Zhang Ze-Yan ZY Li Shang-Ze SZ Zhang Hui-Hui HH Wu Qu-Ran QR Gong Jun J Liang Tong T Gao Lu L Xing Na-Na NN Liu Wen-Bin WB Du Run-Lei RL Zhang Xiao-Dong XD

Molecular and cellular biology 20141215 5

Interleukin-1β (IL-1β) is a key proinflammatory cytokine that initiates several signaling cascades, including those involving CCAAT/enhancer binding proteins (C/EBPs). The mechanism by which IL-1β 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-1β-induced C/EBP activation ...[more]

PMID: 25512613

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Dataset Information

Stabilization of ATF5 by TAK1-Nemo-like kinase critically regulates the interleukin-1?-stimulated C/EBP signaling pathway.

Publications

Stabilization of ATF5 by TAK1-Nemo-like kinase critically regulates the interleukin-1β-stimulated C/EBP signaling pathway.

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