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

作者：Zhang, Ze-Yan; Li, Shang-Ze; Zhang, Hui-Hui; Wu, Qu-Ran; Gong, Jun; Liang, Tong; Gao, Lu; Xing, Na-Na; Liu, Wen-Bin; Du, Run-Lei^*; Zhang, Xiao-Dong

来源：Molecular and Cellular Biology, 2015, 35(5): 778-788.

DOI：10.1128/MCB.01228-14

• NEMO-LIKE KINASE
• MAP KINASE
• TRANSCRIPTION
• BETA
• PROTEIN
• TAK1
• DEGRADATION
• UBIQUITIN
• BINDING
• DELTA

Interleukin-1 beta (IL-1 beta) 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 beta 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 beta-induced C/EBP activation was positively regulated by NLK. Overexpression of NLK activated C/EBP and potentiated IL-1 beta-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 beta 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 beta-triggered C/EBP activation though stabilization of ATF5.

• 出版日期2015-3
• 单位武汉大学; 武汉轻工大学; 华中科技大学