Nemo-like kinase (NLK) negatively regulates NF-kappa B activity through disrupting the interaction of TAK1 with IKKβ.
Stringent negative regulation of the transcription factor NF-κB is essential for maintaining cellular stress responses and homeostasis. However, the tight regulation mechanisms of IKKβ are still not clear. Here, we reported that nemo-like kinase (NLK) is a suppressor of tumor necrosis factor (TNFα)-induced NF-κB signaling by inhibiting the phosphorylation of IKKβ. Overexpression of NLK largely blocked TNFα-induced NF-κB activation, p65 nuclear localization and IκBα degradation; whereas genetic inactivation of NLK showed opposing results. Mechanistically, we identified that NLK interacted with IκB kinase (IKK)-associated complex, which in turn inhibited the assembly of the TAK1/IKKβ and thereby, diminished the IκB kinase phosphorylation. Our results indicate that NLK functions as a pivotal negative regulator in TNFα-induced activation of NF-κB via disrupting the interaction of TAK1 with IKKβ.
College of Life Sciences, Wuhan University, Wuhan 430072, China.
Shang-Ze
SZ
Li
College of Life Sciences, Wuhan University, Wuhan 430072, China.
Hui-Hui
HH
Zhang
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Tsinghua University, Beijing 100005, China.
Jun-Bo
JB
Liang
College of Life Sciences, Wuhan University, Wuhan 430072, China.
Yang
Y
Song
College of Life Sciences, Wuhan University, Wuhan 430072, China.
Bing-Xue
BX
Jin
College of Life Sciences, Wuhan University, Wuhan 430072, China.
Na-Na
NN
Xing
Department of Pharmacology & Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Guo-Chang
GC
Fan
College of Life Sciences, Wuhan University, Wuhan 430072, China. Electronic address: runleidu@whu.edu.cn.
Run-Lei
RL
Du
College of Life Sciences, Wuhan University, Wuhan 430072, China. Electronic address: zhangxd@whu.edu.cn.
Xiao-Dong
XD
Zhang
D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099151:MAP Kinase Kinase Kinase 7
D051550:I-kappa B Kinase; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C470551:NLK protein, human; C496560:IKBKB protein, human
IKKβ; NF-κB; NLK; TAK1; TNFα