title: Stabilization of ATF5 by TAK1-Nemo-like kinase critically regulates the interleukin-1β-stimulated C/EBP signaling pathway.
abstract: 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.
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Ze-Yan
authors.initials: ZY
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Shang-Ze
authors.initials: SZ
authors.lastname: Li
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Hui-Hui
authors.initials: HH
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Qu-Ran
authors.initials: QR
authors.lastname: Wu
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Gong
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Liang
authors.affiliation: Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Gao
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Na-Na
authors.initials: NN
authors.lastname: Xing
authors.affiliation: College of Health Sciences and Nursing, Wuhan Polytechnic University, Wuhan, China.
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Liu
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China runleidu@whu.edu.cn zhangxd@whu.edu.cn.
authors.forename: Run-Lei
authors.initials: RL
authors.lastname: Du
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China runleidu@whu.edu.cn zhangxd@whu.edu.cn.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhang
mesh_terms: D051696:Activating Transcription Factors / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006801:Humans; D053583:Interleukin-1beta / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D051696:Activating Transcription Factors; D022762:CCAAT-Enhancer-Binding Proteins; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D008156:Luciferases; D020930:MAP Kinase Kinase Kinases; D017346:Protein Serine-Threonine Kinases; D000099151:MAP Kinase Kinase Kinase 7; C507532:ATF5 protein, human; C508585:IL1B protein, human; C470551:NLK protein, human