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

Zhang Z.Y., Li S.Z., Zhang H.H., Wu Q.R., Gong J., Liang T., Gao L., Xing N.N., Liu W.B., Du R.L., Zhang X.D.

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 was positively regulated by NLK. Overexpression of NLK activated C/EBP and potentiated IL-1β-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-1β 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-1β-triggered C/EBP activation though stabilization of ATF5.

Mol. Cell. Biol. 35:778-788(2015) [PubMed] [Europe PMC]

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