Stabilization of ATF5 by TAK1–Nemo-Like Kinase Critically Regulates the Interleukin-1-Stimulated C/EBP Signaling Pathway

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 re-mained elusive. Nemo-like kinase (NLK) is a mitogen-activated protein kinase (MAPK)-like kinase associated with many path-ways 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 ac-tivation, 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 defi-ciency 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. Nemo-like kinase (NLK), an evolutionarily conserved mito-gen-activated protein kinase (MAPK)-related serine/threo-nine kinase, plays crucial roles in embryonic patterning, develop-ment, inflammation, and the DNA damage response (DDR) by modulating multiple signaling pathways (1–7). Several report